Article Lead Author Fitzgerald Maria Date Article Developmental Neuroanatomy and Neurophysiology of Pain

1 Pain felt at

a If the article specifically asserts unborn children feel pain at what postshy

fertilization age

b Page 12 Left Column First Paragraph there is little doubt that pain

responses exist even in the youngest preterm infant

2 Nociceptors

a Ifthe article states nociceptors are present at what post-fertilization age

b Page 12 Left Column Second Paragraph The properties of the peripheral

nociceptors at birth are analogous to those of mature nociceptors

3 Thalamus link

a If the article states nerves link nociceptors to the thalamus at what postshy

fertilization age

b Page

4 Subcortical plate link

a If the article states nerves link to the subcortical plate at what post-fertilization

age

b Page

5 Noxious stimuli reaction

a Does the article refer to reaction to noxious stimuli At what post-fertilization

age

b Page

6 Stress hormones

a Does the article refer to increase in stress hormones with noxious stimuli At

what post-fertilization age

b Page

7 Long-term effects

a Does the article describe long term harmful effects from exposure to noxious

stimuli

b Page

8 Fetal anesthesia

a Does the article refer to use of fetal anesthesia and its effect At what postshy

fertilization age

b Page 15 Left Column Second Paragraph This response is a permanent one

whereby the injury results in a structural and functional reorganization of the

nervous system and alters the final adult pattern of connections

Page 15 Left Column Third Paragraph However in many cases developing

neural processes require particular conditions at critical times in order to

develop normally

9 Cortex

a Does the article relate to the asserted need for cortical involvement to

experience pain How

b Page

10 OTHER

a Page 12 Right Column Last Paragraph Recent evidence has shown that the

cingulated gyrus is especially important in the emotional and attentional

aspect of pain and it would be interesting to know something of the

development of this region

2 Developmental Neuroanatomy and Neurophysiology of Pain

Maria Fitzgerald KJS Anand

Although the study of the developmental neurobiology of pain pathways is stili very new we are beginning to gain some insights into how pain responses become organized in infancy In this chapter our present knowledge of the structural and functional development of pain pathways will be re shyviewed To do this effectively we have drawn on principles established in two other areas of neurobiology The first of these is the general developmental processes that underlie the growth and maturation of the nervous system These are important beshycause they provide the context within which immature pain mechanisms are operating The second is the study of adult pain path shyways which are important because they provide an end point toward which develshyoping pain pathways are heading Research shyers interested in pediatric pain need to keep abreast of advances in both these areas to fully comprehend how infants and children respond to pain and to noxious stimuli

Much of our knowledge of the basic bi shyology of pain development has been ob shytained from studies on laboratory rats Rats ~nd h umans have different developmental ~lmeta bles but the basic sequence of events In the ma tura tion of sensory systems are the sam in both species Comparative studies of somatos nsory and motor development show that a lthough rats are relatively im shyma ture at birth at approximately the same stage as a hu man infan t is at 24 weeks ges shyta tIOnal age rats d velopment is h igh ly ac shycelerated (1) For th purpose of this chapter therefore data obtained from newborn rats relate to prematu r human infants and data from 2- to 3-week-old rats to infants d uring their first year

TIME COURSE OF PAIN RESPONSES In the mid-1980s an important change took place in the study of pain Patrick Wall pu----_ lished a paper entitled Future Trends in Pain Research (2) in which he pointed out that the scientific study of pain had been reshystricted to the instant events that follow a noxious stimulus and that while these events were important clinical pain often inshyvolved much longer-term events Pain it was argued falls into different time epshyochs-the immediate pain lasting seconds or minutes the medium-term pain lasting hours or days and the longer-term pain lastshying weeks or years Although all three epshyochs are important they are not equal in terms of human anguish The mechanisms involved may be the same for each epoch differing only in time course but it is becomshying increasingly evident that different mech shyanisms are involved in longer-term acute and chronic pain Now in the early 1990s we are becoming more aware of the ability of the nervous system to switch on long shylasting changes in response to certain stimuli and we are increasing our research into such longterm responses to noxous s timuli (3 4)

IMMEDIATE PAIN RESPONSE A noxious stimulus results in an immediate response in both the somatic and autonomic nervous systems (Fig 21A) In many cases the response is a pro tective one su h s the withdrawal flexion refl x That uch pail reshyponses exi t in neonates has been a subject

of considerable study (5-9) Despite some

11

___~

12 1 Theoretical Background

variability and a certain lack of spedfidty in-the responses resulting in difficulties in meashysurement there is little doubt that pain reshysponses exist even in the youngest pretenn infant

Examination of the anatomical and physshyiological development of the pathways inshy

------_ -YQI-yeg tn the~~E~eo~~es reveals that neural elements are in place frama-neaTly Stageofmiddotmiddotshydevelopment and continue to mature well into postnatal life In the rat peripheral noshyciceptors both those with Ao and C fibers develop soon after cutaneous axons reach the skin early in fetal life (10) The propershyties of the peripheral nociceptors at birth are analogous to those of mature nociceptors (11) Large diameter dorsal root fibers grow into the cord first and small diameter C fibers later just before birth The response of fetal

----- ---- dors-al -horn-neurons--to-botMm~ing-and pinching the skin must therefore be transshymitted by large A fibers (12) When A fibers grow into the spinal cord they rapidly proshyduce synaptically evoked activity in dorsal hom cells however this is not true of C fishybers which do not produce spikes in dorsal hom neurones until the end of the first postshynatal week (13) The reason for the long delay between the arrival of C fibers in the spinal cord and their ability to excite dorsal hom ceUs is not clear It may reflect slow maturation of presynaptic (14) or postsynshyaptic (15) elements in the neonatal spinal cord inadequate transmitter levels (16) or immature pharmacological receptor propershyties (17)

The functional importance of this long delay in C fiber functional maturation lies in the fact that C fibers are the main group of nociceptors responsible for transmitting chemical and thermal as well as mechanical noxious inputs to the central nervous sysshytem Thus the peripheral nociceptors are unable to produce a rapid postsynaptic spike response in the CNS that will be propagated to rugher levels even though the peripheral receptors can recognize pain When C fi shyb r do begin to evoke rapid spike responses centrally they still require a consid rable peshynod of time to mature Indeed levels of neushyropeptides such as su bs tance P ( P) in small diameter sensory afferents reach adul llevels at about P (postnatal day) 2 1 ( 16) whereas SP receptor d istri ution is not dense and widesprea d until P60 (17) This results in

- very slow synaptic-ttansmission-with-pro--shylonged synaptic delays rapid adaption and habituation for some considerable time (12 18) Furthermore lack of local inhibitory lIrul control produces large receptive fields and ~

activatiprolonged responses during the postnatal immature nperiod (18) Thus the after-discharge of a pathl dorsal nom cell is often greater than its initial

-Tesponse--t~ti-m-ulus--Jnpoundactjhepro-ltiuJ ___ ____ __ _ _ tion of large receptive fields and prolonged responses might increase the chance of transmission in a weakly connected system because it greatly reduces precision and inshycreases preservation of stimulus timing and intensity Local spinal intemeurones in subshystantia gelatinosa are the last spinal neuron system to mature only beginning postnashytally (15) Levels of enkephalin a neuropepshytide in many of these neurons and known to inhibU C-flber transmitter releas~ are very low in the neonatal cord(IOl aann(idntrrhifemiddotjpi1io[)stt-~- middot--------------~ natal opiate receptor changes in sensitivity and distribution are considerable (19 20)

It is not clear whether central postsynapshytic excitation by C fibers is equally immature in the human neonate however immaturity may be one explanation for the somewhat unreliable nature of the immediate newbom pain response and the difficulty in measurshying a consistent change to noxious stimuli

Immediate pain responses at higher levels of the nervous system will of course deshypend on the output of the spinal cord (or equivalent levels of the trigeminal system) Little is known of the maturation of projecshytion pathways and of thalamic and cortical connections in relation to pain processing In the rat spinal cord projection cells develop prenatally and their axons reach the thalashymus around birth (15) in the human spinal cord lamina I (some of which project rosshytrally) cells are mature by 25 weeks (21) Evoked potentials in the rat somatosensory cort x from the forepaw develop the adult form by P12 (22) Evoked potentials in hu- Figure 21 mans suggest that thalamic inputs reach the to the foot a

spinal cordcortex at 29 weeks (23) and this is supported velopmen t by anatomical studies (24) Unfortunately tablished pithis tells us little about the analysis of noxshyterminals I

ious inputs in the infant cortex Recent evishy peralgesia i dence has shown tha t the cingula te gyrus is sidered C especially importan t in the emotiona l and al - dam ge of I tentional aspect of pain (2526) and it wou ld tionaI reorg be int resting to know something of the de- to p rmanc ve lopm nt of this regi n

Page 15 Left Column Third Paragraph However in many cases developing

neural processes require particular conditions at critical times in order to

develop normally

9 Cortex

a Does the article relate to the asserted need for cortical involvement to

experience pain How

b Page

10 OTHER

a Page 12 Right Column Last Paragraph Recent evidence has shown that the

cingulated gyrus is especially important in the emotional and attentional

aspect of pain and it would be interesting to know something of the

development of this region

2 Developmental Neuroanatomy and Neurophysiology of Pain

Maria Fitzgerald KJS Anand

Although the study of the developmental neurobiology of pain pathways is stili very new we are beginning to gain some insights into how pain responses become organized in infancy In this chapter our present knowledge of the structural and functional development of pain pathways will be re shyviewed To do this effectively we have drawn on principles established in two other areas of neurobiology The first of these is the general developmental processes that underlie the growth and maturation of the nervous system These are important beshycause they provide the context within which immature pain mechanisms are operating The second is the study of adult pain path shyways which are important because they provide an end point toward which develshyoping pain pathways are heading Research shyers interested in pediatric pain need to keep abreast of advances in both these areas to fully comprehend how infants and children respond to pain and to noxious stimuli

Much of our knowledge of the basic bi shyology of pain development has been ob shytained from studies on laboratory rats Rats ~nd h umans have different developmental ~lmeta bles but the basic sequence of events In the ma tura tion of sensory systems are the sam in both species Comparative studies of somatos nsory and motor development show that a lthough rats are relatively im shyma ture at birth at approximately the same stage as a hu man infan t is at 24 weeks ges shyta tIOnal age rats d velopment is h igh ly ac shycelerated (1) For th purpose of this chapter therefore data obtained from newborn rats relate to prematu r human infants and data from 2- to 3-week-old rats to infants d uring their first year

TIME COURSE OF PAIN RESPONSES In the mid-1980s an important change took place in the study of pain Patrick Wall pu----_ lished a paper entitled Future Trends in Pain Research (2) in which he pointed out that the scientific study of pain had been reshystricted to the instant events that follow a noxious stimulus and that while these events were important clinical pain often inshyvolved much longer-term events Pain it was argued falls into different time epshyochs-the immediate pain lasting seconds or minutes the medium-term pain lasting hours or days and the longer-term pain lastshying weeks or years Although all three epshyochs are important they are not equal in terms of human anguish The mechanisms involved may be the same for each epoch differing only in time course but it is becomshying increasingly evident that different mech shyanisms are involved in longer-term acute and chronic pain Now in the early 1990s we are becoming more aware of the ability of the nervous system to switch on long shylasting changes in response to certain stimuli and we are increasing our research into such longterm responses to noxous s timuli (3 4)

IMMEDIATE PAIN RESPONSE A noxious stimulus results in an immediate response in both the somatic and autonomic nervous systems (Fig 21A) In many cases the response is a pro tective one su h s the withdrawal flexion refl x That uch pail reshyponses exi t in neonates has been a subject

of considerable study (5-9) Despite some

11

___~

12 1 Theoretical Background

variability and a certain lack of spedfidty in-the responses resulting in difficulties in meashysurement there is little doubt that pain reshysponses exist even in the youngest pretenn infant

Examination of the anatomical and physshyiological development of the pathways inshy

------_ -YQI-yeg tn the~~E~eo~~es reveals that neural elements are in place frama-neaTly Stageofmiddotmiddotshydevelopment and continue to mature well into postnatal life In the rat peripheral noshyciceptors both those with Ao and C fibers develop soon after cutaneous axons reach the skin early in fetal life (10) The propershyties of the peripheral nociceptors at birth are analogous to those of mature nociceptors (11) Large diameter dorsal root fibers grow into the cord first and small diameter C fibers later just before birth The response of fetal

----- ---- dors-al -horn-neurons--to-botMm~ing-and pinching the skin must therefore be transshymitted by large A fibers (12) When A fibers grow into the spinal cord they rapidly proshyduce synaptically evoked activity in dorsal hom cells however this is not true of C fishybers which do not produce spikes in dorsal hom neurones until the end of the first postshynatal week (13) The reason for the long delay between the arrival of C fibers in the spinal cord and their ability to excite dorsal hom ceUs is not clear It may reflect slow maturation of presynaptic (14) or postsynshyaptic (15) elements in the neonatal spinal cord inadequate transmitter levels (16) or immature pharmacological receptor propershyties (17)

The functional importance of this long delay in C fiber functional maturation lies in the fact that C fibers are the main group of nociceptors responsible for transmitting chemical and thermal as well as mechanical noxious inputs to the central nervous sysshytem Thus the peripheral nociceptors are unable to produce a rapid postsynaptic spike response in the CNS that will be propagated to rugher levels even though the peripheral receptors can recognize pain When C fi shyb r do begin to evoke rapid spike responses centrally they still require a consid rable peshynod of time to mature Indeed levels of neushyropeptides such as su bs tance P ( P) in small diameter sensory afferents reach adul llevels at about P (postnatal day) 2 1 ( 16) whereas SP receptor d istri ution is not dense and widesprea d until P60 (17) This results in

- very slow synaptic-ttansmission-with-pro--shylonged synaptic delays rapid adaption and habituation for some considerable time (12 18) Furthermore lack of local inhibitory lIrul control produces large receptive fields and ~

activatiprolonged responses during the postnatal immature nperiod (18) Thus the after-discharge of a pathl dorsal nom cell is often greater than its initial

-Tesponse--t~ti-m-ulus--Jnpoundactjhepro-ltiuJ ___ ____ __ _ _ tion of large receptive fields and prolonged responses might increase the chance of transmission in a weakly connected system because it greatly reduces precision and inshycreases preservation of stimulus timing and intensity Local spinal intemeurones in subshystantia gelatinosa are the last spinal neuron system to mature only beginning postnashytally (15) Levels of enkephalin a neuropepshytide in many of these neurons and known to inhibU C-flber transmitter releas~ are very low in the neonatal cord(IOl aann(idntrrhifemiddotjpi1io[)stt-~- middot--------------~ natal opiate receptor changes in sensitivity and distribution are considerable (19 20)

It is not clear whether central postsynapshytic excitation by C fibers is equally immature in the human neonate however immaturity may be one explanation for the somewhat unreliable nature of the immediate newbom pain response and the difficulty in measurshying a consistent change to noxious stimuli

Immediate pain responses at higher levels of the nervous system will of course deshypend on the output of the spinal cord (or equivalent levels of the trigeminal system) Little is known of the maturation of projecshytion pathways and of thalamic and cortical connections in relation to pain processing In the rat spinal cord projection cells develop prenatally and their axons reach the thalashymus around birth (15) in the human spinal cord lamina I (some of which project rosshytrally) cells are mature by 25 weeks (21) Evoked potentials in the rat somatosensory cort x from the forepaw develop the adult form by P12 (22) Evoked potentials in hu- Figure 21 mans suggest that thalamic inputs reach the to the foot a

spinal cordcortex at 29 weeks (23) and this is supported velopmen t by anatomical studies (24) Unfortunately tablished pithis tells us little about the analysis of noxshyterminals I

ious inputs in the infant cortex Recent evishy peralgesia i dence has shown tha t the cingula te gyrus is sidered C especially importan t in the emotiona l and al - dam ge of I tentional aspect of pain (2526) and it wou ld tionaI reorg be int resting to know something of the de- to p rmanc ve lopm nt of this regi n

2 Developmental Neuroanatomy and Neurophysiology of Pain

Maria Fitzgerald KJS Anand

Although the study of the developmental neurobiology of pain pathways is stili very new we are beginning to gain some insights into how pain responses become organized in infancy In this chapter our present knowledge of the structural and functional development of pain pathways will be re shyviewed To do this effectively we have drawn on principles established in two other areas of neurobiology The first of these is the general developmental processes that underlie the growth and maturation of the nervous system These are important beshycause they provide the context within which immature pain mechanisms are operating The second is the study of adult pain path shyways which are important because they provide an end point toward which develshyoping pain pathways are heading Research shyers interested in pediatric pain need to keep abreast of advances in both these areas to fully comprehend how infants and children respond to pain and to noxious stimuli

Much of our knowledge of the basic bi shyology of pain development has been ob shytained from studies on laboratory rats Rats ~nd h umans have different developmental ~lmeta bles but the basic sequence of events In the ma tura tion of sensory systems are the sam in both species Comparative studies of somatos nsory and motor development show that a lthough rats are relatively im shyma ture at birth at approximately the same stage as a hu man infan t is at 24 weeks ges shyta tIOnal age rats d velopment is h igh ly ac shycelerated (1) For th purpose of this chapter therefore data obtained from newborn rats relate to prematu r human infants and data from 2- to 3-week-old rats to infants d uring their first year

TIME COURSE OF PAIN RESPONSES In the mid-1980s an important change took place in the study of pain Patrick Wall pu----_ lished a paper entitled Future Trends in Pain Research (2) in which he pointed out that the scientific study of pain had been reshystricted to the instant events that follow a noxious stimulus and that while these events were important clinical pain often inshyvolved much longer-term events Pain it was argued falls into different time epshyochs-the immediate pain lasting seconds or minutes the medium-term pain lasting hours or days and the longer-term pain lastshying weeks or years Although all three epshyochs are important they are not equal in terms of human anguish The mechanisms involved may be the same for each epoch differing only in time course but it is becomshying increasingly evident that different mech shyanisms are involved in longer-term acute and chronic pain Now in the early 1990s we are becoming more aware of the ability of the nervous system to switch on long shylasting changes in response to certain stimuli and we are increasing our research into such longterm responses to noxous s timuli (3 4)

IMMEDIATE PAIN RESPONSE A noxious stimulus results in an immediate response in both the somatic and autonomic nervous systems (Fig 21A) In many cases the response is a pro tective one su h s the withdrawal flexion refl x That uch pail reshyponses exi t in neonates has been a subject

of considerable study (5-9) Despite some

11

___~

12 1 Theoretical Background

variability and a certain lack of spedfidty in-the responses resulting in difficulties in meashysurement there is little doubt that pain reshysponses exist even in the youngest pretenn infant

Examination of the anatomical and physshyiological development of the pathways inshy

------_ -YQI-yeg tn the~~E~eo~~es reveals that neural elements are in place frama-neaTly Stageofmiddotmiddotshydevelopment and continue to mature well into postnatal life In the rat peripheral noshyciceptors both those with Ao and C fibers develop soon after cutaneous axons reach the skin early in fetal life (10) The propershyties of the peripheral nociceptors at birth are analogous to those of mature nociceptors (11) Large diameter dorsal root fibers grow into the cord first and small diameter C fibers later just before birth The response of fetal

----- ---- dors-al -horn-neurons--to-botMm~ing-and pinching the skin must therefore be transshymitted by large A fibers (12) When A fibers grow into the spinal cord they rapidly proshyduce synaptically evoked activity in dorsal hom cells however this is not true of C fishybers which do not produce spikes in dorsal hom neurones until the end of the first postshynatal week (13) The reason for the long delay between the arrival of C fibers in the spinal cord and their ability to excite dorsal hom ceUs is not clear It may reflect slow maturation of presynaptic (14) or postsynshyaptic (15) elements in the neonatal spinal cord inadequate transmitter levels (16) or immature pharmacological receptor propershyties (17)

The functional importance of this long delay in C fiber functional maturation lies in the fact that C fibers are the main group of nociceptors responsible for transmitting chemical and thermal as well as mechanical noxious inputs to the central nervous sysshytem Thus the peripheral nociceptors are unable to produce a rapid postsynaptic spike response in the CNS that will be propagated to rugher levels even though the peripheral receptors can recognize pain When C fi shyb r do begin to evoke rapid spike responses centrally they still require a consid rable peshynod of time to mature Indeed levels of neushyropeptides such as su bs tance P ( P) in small diameter sensory afferents reach adul llevels at about P (postnatal day) 2 1 ( 16) whereas SP receptor d istri ution is not dense and widesprea d until P60 (17) This results in

- very slow synaptic-ttansmission-with-pro--shylonged synaptic delays rapid adaption and habituation for some considerable time (12 18) Furthermore lack of local inhibitory lIrul control produces large receptive fields and ~

activatiprolonged responses during the postnatal immature nperiod (18) Thus the after-discharge of a pathl dorsal nom cell is often greater than its initial

-Tesponse--t~ti-m-ulus--Jnpoundactjhepro-ltiuJ ___ ____ __ _ _ tion of large receptive fields and prolonged responses might increase the chance of transmission in a weakly connected system because it greatly reduces precision and inshycreases preservation of stimulus timing and intensity Local spinal intemeurones in subshystantia gelatinosa are the last spinal neuron system to mature only beginning postnashytally (15) Levels of enkephalin a neuropepshytide in many of these neurons and known to inhibU C-flber transmitter releas~ are very low in the neonatal cord(IOl aann(idntrrhifemiddotjpi1io[)stt-~- middot--------------~ natal opiate receptor changes in sensitivity and distribution are considerable (19 20)

It is not clear whether central postsynapshytic excitation by C fibers is equally immature in the human neonate however immaturity may be one explanation for the somewhat unreliable nature of the immediate newbom pain response and the difficulty in measurshying a consistent change to noxious stimuli

Immediate pain responses at higher levels of the nervous system will of course deshypend on the output of the spinal cord (or equivalent levels of the trigeminal system) Little is known of the maturation of projecshytion pathways and of thalamic and cortical connections in relation to pain processing In the rat spinal cord projection cells develop prenatally and their axons reach the thalashymus around birth (15) in the human spinal cord lamina I (some of which project rosshytrally) cells are mature by 25 weeks (21) Evoked potentials in the rat somatosensory cort x from the forepaw develop the adult form by P12 (22) Evoked potentials in hu- Figure 21 mans suggest that thalamic inputs reach the to the foot a

spinal cordcortex at 29 weeks (23) and this is supported velopmen t by anatomical studies (24) Unfortunately tablished pithis tells us little about the analysis of noxshyterminals I

ious inputs in the infant cortex Recent evishy peralgesia i dence has shown tha t the cingula te gyrus is sidered C especially importan t in the emotiona l and al - dam ge of I tentional aspect of pain (2526) and it wou ld tionaI reorg be int resting to know something of the de- to p rmanc ve lopm nt of this regi n

12 1 Theoretical Background

variability and a certain lack of spedfidty in-the responses resulting in difficulties in meashysurement there is little doubt that pain reshysponses exist even in the youngest pretenn infant

Examination of the anatomical and physshyiological development of the pathways inshy

------_ -YQI-yeg tn the~~E~eo~~es reveals that neural elements are in place frama-neaTly Stageofmiddotmiddotshydevelopment and continue to mature well into postnatal life In the rat peripheral noshyciceptors both those with Ao and C fibers develop soon after cutaneous axons reach the skin early in fetal life (10) The propershyties of the peripheral nociceptors at birth are analogous to those of mature nociceptors (11) Large diameter dorsal root fibers grow into the cord first and small diameter C fibers later just before birth The response of fetal

----- ---- dors-al -horn-neurons--to-botMm~ing-and pinching the skin must therefore be transshymitted by large A fibers (12) When A fibers grow into the spinal cord they rapidly proshyduce synaptically evoked activity in dorsal hom cells however this is not true of C fishybers which do not produce spikes in dorsal hom neurones until the end of the first postshynatal week (13) The reason for the long delay between the arrival of C fibers in the spinal cord and their ability to excite dorsal hom ceUs is not clear It may reflect slow maturation of presynaptic (14) or postsynshyaptic (15) elements in the neonatal spinal cord inadequate transmitter levels (16) or immature pharmacological receptor propershyties (17)

The functional importance of this long delay in C fiber functional maturation lies in the fact that C fibers are the main group of nociceptors responsible for transmitting chemical and thermal as well as mechanical noxious inputs to the central nervous sysshytem Thus the peripheral nociceptors are unable to produce a rapid postsynaptic spike response in the CNS that will be propagated to rugher levels even though the peripheral receptors can recognize pain When C fi shyb r do begin to evoke rapid spike responses centrally they still require a consid rable peshynod of time to mature Indeed levels of neushyropeptides such as su bs tance P ( P) in small diameter sensory afferents reach adul llevels at about P (postnatal day) 2 1 ( 16) whereas SP receptor d istri ution is not dense and widesprea d until P60 (17) This results in

- very slow synaptic-ttansmission-with-pro--shylonged synaptic delays rapid adaption and habituation for some considerable time (12 18) Furthermore lack of local inhibitory lIrul control produces large receptive fields and ~

activatiprolonged responses during the postnatal immature nperiod (18) Thus the after-discharge of a pathl dorsal nom cell is often greater than its initial

-Tesponse--t~ti-m-ulus--Jnpoundactjhepro-ltiuJ ___ ____ __ _ _ tion of large receptive fields and prolonged responses might increase the chance of transmission in a weakly connected system because it greatly reduces precision and inshycreases preservation of stimulus timing and intensity Local spinal intemeurones in subshystantia gelatinosa are the last spinal neuron system to mature only beginning postnashytally (15) Levels of enkephalin a neuropepshytide in many of these neurons and known to inhibU C-flber transmitter releas~ are very low in the neonatal cord(IOl aann(idntrrhifemiddotjpi1io[)stt-~- middot--------------~ natal opiate receptor changes in sensitivity and distribution are considerable (19 20)

It is not clear whether central postsynapshytic excitation by C fibers is equally immature in the human neonate however immaturity may be one explanation for the somewhat unreliable nature of the immediate newbom pain response and the difficulty in measurshying a consistent change to noxious stimuli

Immediate pain responses at higher levels of the nervous system will of course deshypend on the output of the spinal cord (or equivalent levels of the trigeminal system) Little is known of the maturation of projecshytion pathways and of thalamic and cortical connections in relation to pain processing In the rat spinal cord projection cells develop prenatally and their axons reach the thalashymus around birth (15) in the human spinal cord lamina I (some of which project rosshytrally) cells are mature by 25 weeks (21) Evoked potentials in the rat somatosensory cort x from the forepaw develop the adult form by P12 (22) Evoked potentials in hu- Figure 21 mans suggest that thalamic inputs reach the to the foot a

spinal cordcortex at 29 weeks (23) and this is supported velopmen t by anatomical studies (24) Unfortunately tablished pithis tells us little about the analysis of noxshyterminals I

ious inputs in the infant cortex Recent evishy peralgesia i dence has shown tha t the cingula te gyrus is sidered C especially importan t in the emotiona l and al - dam ge of I tentional aspect of pain (2526) and it wou ld tionaI reorg be int resting to know something of the de- to p rmanc ve lopm nt of this regi n

2 Neuroanatomy ald Neuropllysiology of Pain 13

Immediate Response

activation 01 immature nociceptive

pathways

Sensation

-Established Pain Established Pain

Response activation 01

long term processes in immature nociceptive

pathways

~ Sensitization

---~~ - shy _-_ _--_ -shy

J -lttrvoo

Reflexes

Long Term Effects

permanent structural changes in

sensory pathways

Cell I

Sensation

d~

~ ISpoliog

A U

Sensation

Altered excitability

Figure 21 A A schematic diagram of the immediate pain response in the neonate A noxious stimulus to the foot activates nOciceptor primary afferents which in turn produce rapid postsynaptic events in th e spina l cord These can evoke reflexes and excite projection pathways to higher brain centers The deshyvelopment and maturation of all these steps need to be considered B A schematic diagram of the esshyta blished pain response in the neonate An injury in the peripheral tissue will sensitize local nociceptor t ~rmina l s It will also Tesult in altered levels of excitability in central cells leading to tenderness and hyshyperalgesia in the affected area The development and maturation of these mechanisms needs to be conshySid ered C A schematic diagram of the longterm effects of peripheral injury in the newborn Axonal damage of local n rves will lead to permanent cell death in the dorsa l root ga nglia Structural and fun cshytillnal reurganization occurs in th e eNS as a result f sprouting and altered con necti vit y wh ich may lea d t I l perma nent ly altered sensa tion

L J fItUltllLUI vacKground

ESTABUSHED PAIN RESPONSE IN NEONATES

An established pain response is one that outshylasts the initial noxious stimulus (Fig 218) The response lasts for hours and days not seconds and minutes It is this response that is most important clinically and as yet its deshyvelopment has not been well studied Preshymature infants clearly mount a metabolic stress response postoperatively that can be blunted or blocked by the intravenous adshyministration of opioids (27) Crying is inshy

_ ----_ _ creasedJOlsevemltiays-ftgtHmving-circumdc

sion (28) In our own study the sensitivity of the skin of the heel following repeated lancshying over days and weeks was shown to be elshyevated indicating a lasting hyperalgesic reshysponse to the injury (2930)

To understand the mechanisms underlyshying the established pain response and find ways of measuring it we must search for CNS processes that are initially triggered by a noxious stimulus or in but that last for a

nv(vmiddot in esshytablishing a prolonged response to injury inshyvolves sensitization of peripheral sensory reshyceptors In the adult rat monkey and human the threshold of cutaneous nodcepshytors to a noxious stimulus and the magnitude of the response produced by peripheral senshysory receptors can be increased for hours folshylowing injury This occurs whether the in shyjury occurs directly to the receptor or within its receptive field (see reference 31 for reshyview) As yet the ability of immature pe shyripheral n Ociceptors to become sensitized following noxious stimulation is unknown However one related property of peripheral nociceptors namely the production of neushyrogenic edema is not functional in the newshyborn Neurogenic edema is an inflammatory response resulting in plasma extravasation which is produced by antidromic activation of polymodal nociceptors by way of an axon reflex mechanism Newborn rats while pershyfectly capable of producing a nonspecific inshyflammatory response do not develop neushyrogenic edema until PI 0 (32) The reason for this is not know n but may be caused by in shyadequa te levels of the appropriate media shytors

E tablished pain responses are likely to involve centra l m echanisms th erefore it is

important to study the maturation of longshylasting painful events in the spinal cord and brain Several transmitter receptor systems eg for peptides and the glutamate NMDA receptor have been implicated in prolonged postsynaptic responses to noxious stimuli (3 4) Despite low levels of neuropeptides in afshyferent terminals in the newborn stimulation of C fibers does produce substance P release in the neonatal spinal cord (33) Furthershymore stimulationmiddot of C fibers produces a long-lasting depolarization of motoneurons that far outlasts the stimIl~(31)S1Jch_a_de pOliiiiZanon-lslifocked by SP antagonists (33) and might be expected to result in longshylasting changes in excitability of those moshytoneurons In the dorsal hom where as disshycussed above C-fiber stimulation in the neshyonate does not produce a spike response that can be propagated to higher levels (13) such long-lasting changes in excitability have been demonstrated Mustard oil a specific C-fiber stimulus has no direct effect on neoshynal dOIial horn cellsbut doesincrease middottheirshy

noxious stimuli (1) an increase In censhytral excitability is analogous to that proposed in the adult to underlie hypersensitivity or allodynia in the site of an injury (3 4)

A search for molecular and chemical changes underlying persistent neuronal changes in the CNS has led to considerable interest in the role of proto-oncogenes such as c-fos as third messengers in longterm responses In the adult c-fos is rapidly exshypressed in the spinal cord brainstem nuclei thalamus and cortex following noxious stimulation or injury (for review see refershyence 35) A similar expression is seen in newshyborn rats (36) following peripheral injury but not with pure C-fiber stimuli

In adults established pain responses are thought to also involve activation of a num shyber of endogenous pain control systems One of these is the descending inhibitory fiber tracts from the brainstem which act to reduce the activity of spinal-cord cells evoked by noxious inputs (37) This system is not functional in the newborn and only begins its actions on postnatal day 10 (38) The reason for this is unclear because the deshyscending axon tracts are apparently present from before birth (39) The delayed postnashytal function likely reflects low transmitter levels (40) or low pharmacological receptor

function gt~ mechani~ which d

newbornf cating fa apses an sion dUll might bE recepton onstrate( appearar tions nei it may nc findings knowled

LONG TISSUl

A third I

beyond I

- - - - -__-

nervouS tern of CI

It is ( nervous ery than cases d particula to devel( is the del sory neu tissues d sensory stage of will be CI

of the de trophic S

by nervE duced in to the c( from ax nous N( only tru cells m( spinal c( cut off I men Ft onal da nerve dt going be

2 Neuroanatomy alld Nellrophysiology of Pain 15

function A further endogenous control ies The death of these peripheral neurons mechanism is the release of endorphins leaves an area of deafferentation in the spishywhich does appear to be established in the nal cord This causes severe retardation of newborn (see reference 7) Further complishy postsynaptic growth and the somadendritic cating factors are the role of transient synshy development of second order spinal-cord apses and receptor and transmitter expresshy cells is virtually arrested (45) Furthermore sion during development Examples of this nearby intact sensory neurons send collatshymight be high-density or poorly organized eral sprouts considerable distances into the receptors (17) or as has recently been demshy deafferented area of the cord and form synshyonstrated in the developing spinal cord the aptic connections within the region (46 47) appearance of functional receptor popula- This means that now totally inappropriate

tQI1snever seen in the adult (41) As a result cord regions normally devoted to inputs it may not alwciysbeappropriiite fo iriterpnl from the damaged area are processing inshyfindings in the immature CNS in the light of formation from nearby undamaged skin In knowledge of adult mechanisms other words the nearby skin areas have a

greater than normal representation in the CNS This reorganization is also observed in

LONGTERM RESPONSES TO the trigeminal regions following facial injushyTISSUE INJURY ries (48) The effects are not restricted to the

first synapse either but continue on up A third type of response to injury goes far through the CNS Peripheral nerve injury in beyond the immediate and established pain the neonate alters connections in the thalashyresponses discussed in the pryi9u~ secti9ns mus and the somatosensory cortex (49 SO)

---------~~-kJ~)~~~~~~s~m~~~s~a-~~tinaI~nL--f~~~~~ll~~~orgrr~0n~p~~middot~~~ti~middotb~n~o~f--middot middot middot middot middot middot middot ----~ one whereby the in results a struc- the bOdy surface or map tural and functional reorganization of the brain Secondary transneuronal degenerashynervous system and alters the final adult pat- tion even of the corticospinal tract (CST) has tern of connections been induced after nerve section in newborn

It is commonly thought that the infant rats (51) nervous system has greater powers of recov- These longterm consequences of injury in ery than that of the adult However in many laboratory rats are not simply early embryshycases developing neural processes require ological events of interest to developmental particular conditions at critical times in order biologists but have important implications to develop normally (42) An example of this in human premature and full-term infants is the dependence on trophic support of sen- who undergo painful experiences For exshysory neurons provided by peripheral target ample traumatic interventions of the kind tissues during development If a cutaneous that are necessarily undertaken in neonatal sensory axon is damaged during a critical intensive-care wards may well cause a simishystage of d evelopment this essential support lar reorganization in the somatosensory and will be cut off and result in irreversible dea th motor svstems as are seen in the rat model of the dorsal root ganglion cells (43 44) The While ~e are discovering the nature of the trophic support is provided at least in part new functional connections that can be by nerve growth factor (NGF) which is pro- formed in the rat we still remain ignorant of duced in target tissues and transported back what if any sensory disturbances such re-to the cell bodies The cell death resulting organization may cause in human infants from axotomy can be prevented by exoge- ObviousIv more research both in the laboshynous NGF administration (43) This is not ratary and clinical setting is needed to fur-only true of peripheral sensory ganglion ther expa nd Our knowledge in this area cells m toneurons and central cells in th e spinal cord and brain die if their axons are APPLIED PHYSIOLOGY OF PAINcut o ff from their targe ts during developshymen t Furthermore the consequences of axshy The previous sections describe experimental onal damage t even a small p riphera l stu dies of the developmen tal neuroanatomy nerve during developme nt are fa r-reach ing a nd neuro physiology of the pain system de shygoing beyond the death of its own cell bod - ta ilin g the effects of nociceptive stimuli in

-

2 I Neuroanatomy and Nellrophysiology of Pain I 15

function ~ further endogenous control mechanism is the release of endorphins

which does ~ppe~r to be established in the ~bom (see reference 7) Further complishycating factors are the role of transient synshyapses and receptor and transmitter expresshysion during development Examples of this might be high-density or poorly organized receptors (1 7) or as has recently been demshyonstrated in the developing spinal cord the appearance of functional receptor populashytions never seen in the adult (41) As a result it may not always be appropriate to interpret findings in the immature CNS in the light of knowledge of adult mechanisms

LONGTERM RESPONSES TO TISSUE INJURY

A third type of response to injury goes far beyond the immediate and established pain responses discussed in the previous sections

one whereby the tural and fu reorganization of the nervous system and alters the final adult patshytern of connections

It is commonly thought that the infant nervous system has greater powers of recovshyery than that of the adult However in many cases developing neural processes require particular conditions at critical times in order to develop normally (42) An example of this is the dependence on trophic support of senshysory neurons provided by peripheral target tissues during development If a cutaneous sensory axon is damaged during a critical stage of development this essential support will be cut off and result in irreversible death of the dorsal root ganglion cells (43 44) The trophic support is provided at least in part by nerve growth factor (NGF) which is proshyduced in target tissues and transported back to the cell bodies The cell death resulting from axotomy can be prevented by exogeshynous NGF administration (43) This is not only true of peripheral sensory ganglion cells motoneurons and central cells in the spinal cord and brain die if their axons are cu t off from their targets during develop shyment Furthermore the consequences of axshyonal damage to even a small perip h ra I nerve during developmen t are far-reaching go ing beyond th death of its own cell bod -

ies The death of these peripheral neurons leaves an area of deafferentation in the spishynal cord This causes severe retardation of postsynaptic growth and the somadendritic development of second order spinal-cord cells is virtually arrested (45) Furthermore nearby intact sensory neurons send collatshyeral sprouts considerable distances into the deafferented area of the cord and form synshyaptic connections within the region (4647) This means that now totally inappropriate cord regions normally devoted to inputs from the damaged area are processing inshyformation from nearby undamaged skin In other words the nearby skin areas have a greater than normal representation in the CNS This reorganization is also observed in the trigeminal regions following facial injushyries (48) The effects are not restricted to the first synapse either but continue on up through the CNS Peripheral nerve injury in the neonate alters connections in the thalashymus and the somatosensQry ltQrtex (49 20)

the body surface or somatotopic map in the brain Secondary transneuronal degenerashytion even of the corticospinal tract (CST) has been induced after nerve section in newborn rats (51)

These longterm consequences of injury in laboratory rats are not simply eady embryshyological events of interest to developmental biologists but have important implications in human premature and full-term infants who undergo painful experiences For exshyample traumatic interventions of the kind that are necessarily undertaken in neonatal intensive-care wards may well cause a simishylar reorganization in the somatosensory and motor systems as are seen in the rat model While ~e are discovering the nature of the new functional connections that can be formed in the rat we still remain ignorant of what if any sensory disturbances such reshyorganization may cause in human infants Obviously more research both in the laboshyratory and clinical setting is needed to furshyther expand our knowledge in this area

APPLIED PHYSIOLOGY OF PAIN The previous sections describe experimental studies of the developmental neuroanatomy and neurophysiology of th e pain system deshytailing the effects of nociceptive stimuli in

L J fItUltllLUI vacKground

ESTABUSHED PAIN RESPONSE IN NEONATES

An established pain response is one that outshylasts the initial noxious stimulus (Fig 218) The response lasts for hours and days not seconds and minutes It is this response that is most important clinically and as yet its deshyvelopment has not been well studied Preshymature infants clearly mount a metabolic stress response postoperatively that can be blunted or blocked by the intravenous adshyministration of opioids (27) Crying is inshy

_ ----_ _ creasedJOlsevemltiays-ftgtHmving-circumdc

sion (28) In our own study the sensitivity of the skin of the heel following repeated lancshying over days and weeks was shown to be elshyevated indicating a lasting hyperalgesic reshysponse to the injury (2930)

To understand the mechanisms underlyshying the established pain response and find ways of measuring it we must search for CNS processes that are initially triggered by a noxious stimulus or in but that last for a

nv(vmiddot in esshytablishing a prolonged response to injury inshyvolves sensitization of peripheral sensory reshyceptors In the adult rat monkey and human the threshold of cutaneous nodcepshytors to a noxious stimulus and the magnitude of the response produced by peripheral senshysory receptors can be increased for hours folshylowing injury This occurs whether the in shyjury occurs directly to the receptor or within its receptive field (see reference 31 for reshyview) As yet the ability of immature pe shyripheral n Ociceptors to become sensitized following noxious stimulation is unknown However one related property of peripheral nociceptors namely the production of neushyrogenic edema is not functional in the newshyborn Neurogenic edema is an inflammatory response resulting in plasma extravasation which is produced by antidromic activation of polymodal nociceptors by way of an axon reflex mechanism Newborn rats while pershyfectly capable of producing a nonspecific inshyflammatory response do not develop neushyrogenic edema until PI 0 (32) The reason for this is not know n but may be caused by in shyadequa te levels of the appropriate media shytors

E tablished pain responses are likely to involve centra l m echanisms th erefore it is

important to study the maturation of longshylasting painful events in the spinal cord and brain Several transmitter receptor systems eg for peptides and the glutamate NMDA receptor have been implicated in prolonged postsynaptic responses to noxious stimuli (3 4) Despite low levels of neuropeptides in afshyferent terminals in the newborn stimulation of C fibers does produce substance P release in the neonatal spinal cord (33) Furthershymore stimulationmiddot of C fibers produces a long-lasting depolarization of motoneurons that far outlasts the stimIl~(31)S1Jch_a_de pOliiiiZanon-lslifocked by SP antagonists (33) and might be expected to result in longshylasting changes in excitability of those moshytoneurons In the dorsal hom where as disshycussed above C-fiber stimulation in the neshyonate does not produce a spike response that can be propagated to higher levels (13) such long-lasting changes in excitability have been demonstrated Mustard oil a specific C-fiber stimulus has no direct effect on neoshynal dOIial horn cellsbut doesincrease middottheirshy

noxious stimuli (1) an increase In censhytral excitability is analogous to that proposed in the adult to underlie hypersensitivity or allodynia in the site of an injury (3 4)

A search for molecular and chemical changes underlying persistent neuronal changes in the CNS has led to considerable interest in the role of proto-oncogenes such as c-fos as third messengers in longterm responses In the adult c-fos is rapidly exshypressed in the spinal cord brainstem nuclei thalamus and cortex following noxious stimulation or injury (for review see refershyence 35) A similar expression is seen in newshyborn rats (36) following peripheral injury but not with pure C-fiber stimuli

In adults established pain responses are thought to also involve activation of a num shyber of endogenous pain control systems One of these is the descending inhibitory fiber tracts from the brainstem which act to reduce the activity of spinal-cord cells evoked by noxious inputs (37) This system is not functional in the newborn and only begins its actions on postnatal day 10 (38) The reason for this is unclear because the deshyscending axon tracts are apparently present from before birth (39) The delayed postnashytal function likely reflects low transmitter levels (40) or low pharmacological receptor

function gt~ mechani~ which d

newbornf cating fa apses an sion dUll might bE recepton onstrate( appearar tions nei it may nc findings knowled

LONG TISSUl

A third I

beyond I

- - - - -__-

nervouS tern of CI

It is ( nervous ery than cases d particula to devel( is the del sory neu tissues d sensory stage of will be CI

of the de trophic S

by nervE duced in to the c( from ax nous N( only tru cells m( spinal c( cut off I men Ft onal da nerve dt going be

2 Neuroanatomy alld Nellrophysiology of Pain 15

function A further endogenous control ies The death of these peripheral neurons mechanism is the release of endorphins leaves an area of deafferentation in the spishywhich does appear to be established in the nal cord This causes severe retardation of newborn (see reference 7) Further complishy postsynaptic growth and the somadendritic cating factors are the role of transient synshy development of second order spinal-cord apses and receptor and transmitter expresshy cells is virtually arrested (45) Furthermore sion during development Examples of this nearby intact sensory neurons send collatshymight be high-density or poorly organized eral sprouts considerable distances into the receptors (17) or as has recently been demshy deafferented area of the cord and form synshyonstrated in the developing spinal cord the aptic connections within the region (46 47) appearance of functional receptor popula- This means that now totally inappropriate

tQI1snever seen in the adult (41) As a result cord regions normally devoted to inputs it may not alwciysbeappropriiite fo iriterpnl from the damaged area are processing inshyfindings in the immature CNS in the light of formation from nearby undamaged skin In knowledge of adult mechanisms other words the nearby skin areas have a

greater than normal representation in the CNS This reorganization is also observed in

LONGTERM RESPONSES TO the trigeminal regions following facial injushyTISSUE INJURY ries (48) The effects are not restricted to the

first synapse either but continue on up A third type of response to injury goes far through the CNS Peripheral nerve injury in beyond the immediate and established pain the neonate alters connections in the thalashyresponses discussed in the pryi9u~ secti9ns mus and the somatosensory cortex (49 SO)

---------~~-kJ~)~~~~~~s~m~~~s~a-~~tinaI~nL--f~~~~~ll~~~orgrr~0n~p~~middot~~~ti~middotb~n~o~f--middot middot middot middot middot middot middot ----~ one whereby the in results a struc- the bOdy surface or map tural and functional reorganization of the brain Secondary transneuronal degenerashynervous system and alters the final adult pat- tion even of the corticospinal tract (CST) has tern of connections been induced after nerve section in newborn

It is commonly thought that the infant rats (51) nervous system has greater powers of recov- These longterm consequences of injury in ery than that of the adult However in many laboratory rats are not simply early embryshycases developing neural processes require ological events of interest to developmental particular conditions at critical times in order biologists but have important implications to develop normally (42) An example of this in human premature and full-term infants is the dependence on trophic support of sen- who undergo painful experiences For exshysory neurons provided by peripheral target ample traumatic interventions of the kind tissues during development If a cutaneous that are necessarily undertaken in neonatal sensory axon is damaged during a critical intensive-care wards may well cause a simishystage of d evelopment this essential support lar reorganization in the somatosensory and will be cut off and result in irreversible dea th motor svstems as are seen in the rat model of the dorsal root ganglion cells (43 44) The While ~e are discovering the nature of the trophic support is provided at least in part new functional connections that can be by nerve growth factor (NGF) which is pro- formed in the rat we still remain ignorant of duced in target tissues and transported back what if any sensory disturbances such re-to the cell bodies The cell death resulting organization may cause in human infants from axotomy can be prevented by exoge- ObviousIv more research both in the laboshynous NGF administration (43) This is not ratary and clinical setting is needed to fur-only true of peripheral sensory ganglion ther expa nd Our knowledge in this area cells m toneurons and central cells in th e spinal cord and brain die if their axons are APPLIED PHYSIOLOGY OF PAINcut o ff from their targe ts during developshymen t Furthermore the consequences of axshy The previous sections describe experimental onal damage t even a small p riphera l stu dies of the developmen tal neuroanatomy nerve during developme nt are fa r-reach ing a nd neuro physiology of the pain system de shygoing beyond the death of its own cell bod - ta ilin g the effects of nociceptive stimuli in

-

2 I Neuroanatomy and Nellrophysiology of Pain I 15

function ~ further endogenous control mechanism is the release of endorphins

which does ~ppe~r to be established in the ~bom (see reference 7) Further complishycating factors are the role of transient synshyapses and receptor and transmitter expresshysion during development Examples of this might be high-density or poorly organized receptors (1 7) or as has recently been demshyonstrated in the developing spinal cord the appearance of functional receptor populashytions never seen in the adult (41) As a result it may not always be appropriate to interpret findings in the immature CNS in the light of knowledge of adult mechanisms

LONGTERM RESPONSES TO TISSUE INJURY

A third type of response to injury goes far beyond the immediate and established pain responses discussed in the previous sections

one whereby the tural and fu reorganization of the nervous system and alters the final adult patshytern of connections

It is commonly thought that the infant nervous system has greater powers of recovshyery than that of the adult However in many cases developing neural processes require particular conditions at critical times in order to develop normally (42) An example of this is the dependence on trophic support of senshysory neurons provided by peripheral target tissues during development If a cutaneous sensory axon is damaged during a critical stage of development this essential support will be cut off and result in irreversible death of the dorsal root ganglion cells (43 44) The trophic support is provided at least in part by nerve growth factor (NGF) which is proshyduced in target tissues and transported back to the cell bodies The cell death resulting from axotomy can be prevented by exogeshynous NGF administration (43) This is not only true of peripheral sensory ganglion cells motoneurons and central cells in the spinal cord and brain die if their axons are cu t off from their targets during develop shyment Furthermore the consequences of axshyonal damage to even a small perip h ra I nerve during developmen t are far-reaching go ing beyond th death of its own cell bod -

ies The death of these peripheral neurons leaves an area of deafferentation in the spishynal cord This causes severe retardation of postsynaptic growth and the somadendritic development of second order spinal-cord cells is virtually arrested (45) Furthermore nearby intact sensory neurons send collatshyeral sprouts considerable distances into the deafferented area of the cord and form synshyaptic connections within the region (4647) This means that now totally inappropriate cord regions normally devoted to inputs from the damaged area are processing inshyformation from nearby undamaged skin In other words the nearby skin areas have a greater than normal representation in the CNS This reorganization is also observed in the trigeminal regions following facial injushyries (48) The effects are not restricted to the first synapse either but continue on up through the CNS Peripheral nerve injury in the neonate alters connections in the thalashymus and the somatosensQry ltQrtex (49 20)

the body surface or somatotopic map in the brain Secondary transneuronal degenerashytion even of the corticospinal tract (CST) has been induced after nerve section in newborn rats (51)

These longterm consequences of injury in laboratory rats are not simply eady embryshyological events of interest to developmental biologists but have important implications in human premature and full-term infants who undergo painful experiences For exshyample traumatic interventions of the kind that are necessarily undertaken in neonatal intensive-care wards may well cause a simishylar reorganization in the somatosensory and motor systems as are seen in the rat model While ~e are discovering the nature of the new functional connections that can be formed in the rat we still remain ignorant of what if any sensory disturbances such reshyorganization may cause in human infants Obviously more research both in the laboshyratory and clinical setting is needed to furshyther expand our knowledge in this area

APPLIED PHYSIOLOGY OF PAIN The previous sections describe experimental studies of the developmental neuroanatomy and neurophysiology of th e pain system deshytailing the effects of nociceptive stimuli in

2 Neuroanatomy alld Nellrophysiology of Pain 15

function A further endogenous control ies The death of these peripheral neurons mechanism is the release of endorphins leaves an area of deafferentation in the spishywhich does appear to be established in the nal cord This causes severe retardation of newborn (see reference 7) Further complishy postsynaptic growth and the somadendritic cating factors are the role of transient synshy development of second order spinal-cord apses and receptor and transmitter expresshy cells is virtually arrested (45) Furthermore sion during development Examples of this nearby intact sensory neurons send collatshymight be high-density or poorly organized eral sprouts considerable distances into the receptors (17) or as has recently been demshy deafferented area of the cord and form synshyonstrated in the developing spinal cord the aptic connections within the region (46 47) appearance of functional receptor popula- This means that now totally inappropriate

tQI1snever seen in the adult (41) As a result cord regions normally devoted to inputs it may not alwciysbeappropriiite fo iriterpnl from the damaged area are processing inshyfindings in the immature CNS in the light of formation from nearby undamaged skin In knowledge of adult mechanisms other words the nearby skin areas have a

greater than normal representation in the CNS This reorganization is also observed in

LONGTERM RESPONSES TO the trigeminal regions following facial injushyTISSUE INJURY ries (48) The effects are not restricted to the

first synapse either but continue on up A third type of response to injury goes far through the CNS Peripheral nerve injury in beyond the immediate and established pain the neonate alters connections in the thalashyresponses discussed in the pryi9u~ secti9ns mus and the somatosensory cortex (49 SO)

---------~~-kJ~)~~~~~~s~m~~~s~a-~~tinaI~nL--f~~~~~ll~~~orgrr~0n~p~~middot~~~ti~middotb~n~o~f--middot middot middot middot middot middot middot ----~ one whereby the in results a struc- the bOdy surface or map tural and functional reorganization of the brain Secondary transneuronal degenerashynervous system and alters the final adult pat- tion even of the corticospinal tract (CST) has tern of connections been induced after nerve section in newborn

It is commonly thought that the infant rats (51) nervous system has greater powers of recov- These longterm consequences of injury in ery than that of the adult However in many laboratory rats are not simply early embryshycases developing neural processes require ological events of interest to developmental particular conditions at critical times in order biologists but have important implications to develop normally (42) An example of this in human premature and full-term infants is the dependence on trophic support of sen- who undergo painful experiences For exshysory neurons provided by peripheral target ample traumatic interventions of the kind tissues during development If a cutaneous that are necessarily undertaken in neonatal sensory axon is damaged during a critical intensive-care wards may well cause a simishystage of d evelopment this essential support lar reorganization in the somatosensory and will be cut off and result in irreversible dea th motor svstems as are seen in the rat model of the dorsal root ganglion cells (43 44) The While ~e are discovering the nature of the trophic support is provided at least in part new functional connections that can be by nerve growth factor (NGF) which is pro- formed in the rat we still remain ignorant of duced in target tissues and transported back what if any sensory disturbances such re-to the cell bodies The cell death resulting organization may cause in human infants from axotomy can be prevented by exoge- ObviousIv more research both in the laboshynous NGF administration (43) This is not ratary and clinical setting is needed to fur-only true of peripheral sensory ganglion ther expa nd Our knowledge in this area cells m toneurons and central cells in th e spinal cord and brain die if their axons are APPLIED PHYSIOLOGY OF PAINcut o ff from their targe ts during developshymen t Furthermore the consequences of axshy The previous sections describe experimental onal damage t even a small p riphera l stu dies of the developmen tal neuroanatomy nerve during developme nt are fa r-reach ing a nd neuro physiology of the pain system de shygoing beyond the death of its own cell bod - ta ilin g the effects of nociceptive stimuli in

-

2 I Neuroanatomy and Nellrophysiology of Pain I 15

function ~ further endogenous control mechanism is the release of endorphins

which does ~ppe~r to be established in the ~bom (see reference 7) Further complishycating factors are the role of transient synshyapses and receptor and transmitter expresshysion during development Examples of this might be high-density or poorly organized receptors (1 7) or as has recently been demshyonstrated in the developing spinal cord the appearance of functional receptor populashytions never seen in the adult (41) As a result it may not always be appropriate to interpret findings in the immature CNS in the light of knowledge of adult mechanisms

LONGTERM RESPONSES TO TISSUE INJURY

A third type of response to injury goes far beyond the immediate and established pain responses discussed in the previous sections

one whereby the tural and fu reorganization of the nervous system and alters the final adult patshytern of connections

It is commonly thought that the infant nervous system has greater powers of recovshyery than that of the adult However in many cases developing neural processes require particular conditions at critical times in order to develop normally (42) An example of this is the dependence on trophic support of senshysory neurons provided by peripheral target tissues during development If a cutaneous sensory axon is damaged during a critical stage of development this essential support will be cut off and result in irreversible death of the dorsal root ganglion cells (43 44) The trophic support is provided at least in part by nerve growth factor (NGF) which is proshyduced in target tissues and transported back to the cell bodies The cell death resulting from axotomy can be prevented by exogeshynous NGF administration (43) This is not only true of peripheral sensory ganglion cells motoneurons and central cells in the spinal cord and brain die if their axons are cu t off from their targets during develop shyment Furthermore the consequences of axshyonal damage to even a small perip h ra I nerve during developmen t are far-reaching go ing beyond th death of its own cell bod -

ies The death of these peripheral neurons leaves an area of deafferentation in the spishynal cord This causes severe retardation of postsynaptic growth and the somadendritic development of second order spinal-cord cells is virtually arrested (45) Furthermore nearby intact sensory neurons send collatshyeral sprouts considerable distances into the deafferented area of the cord and form synshyaptic connections within the region (4647) This means that now totally inappropriate cord regions normally devoted to inputs from the damaged area are processing inshyformation from nearby undamaged skin In other words the nearby skin areas have a greater than normal representation in the CNS This reorganization is also observed in the trigeminal regions following facial injushyries (48) The effects are not restricted to the first synapse either but continue on up through the CNS Peripheral nerve injury in the neonate alters connections in the thalashymus and the somatosensQry ltQrtex (49 20)

the body surface or somatotopic map in the brain Secondary transneuronal degenerashytion even of the corticospinal tract (CST) has been induced after nerve section in newborn rats (51)

These longterm consequences of injury in laboratory rats are not simply eady embryshyological events of interest to developmental biologists but have important implications in human premature and full-term infants who undergo painful experiences For exshyample traumatic interventions of the kind that are necessarily undertaken in neonatal intensive-care wards may well cause a simishylar reorganization in the somatosensory and motor systems as are seen in the rat model While ~e are discovering the nature of the new functional connections that can be formed in the rat we still remain ignorant of what if any sensory disturbances such reshyorganization may cause in human infants Obviously more research both in the laboshyratory and clinical setting is needed to furshyther expand our knowledge in this area

APPLIED PHYSIOLOGY OF PAIN The previous sections describe experimental studies of the developmental neuroanatomy and neurophysiology of th e pain system deshytailing the effects of nociceptive stimuli in

-

2 I Neuroanatomy and Nellrophysiology of Pain I 15

function ~ further endogenous control mechanism is the release of endorphins

which does ~ppe~r to be established in the ~bom (see reference 7) Further complishycating factors are the role of transient synshyapses and receptor and transmitter expresshysion during development Examples of this might be high-density or poorly organized receptors (1 7) or as has recently been demshyonstrated in the developing spinal cord the appearance of functional receptor populashytions never seen in the adult (41) As a result it may not always be appropriate to interpret findings in the immature CNS in the light of knowledge of adult mechanisms

LONGTERM RESPONSES TO TISSUE INJURY

A third type of response to injury goes far beyond the immediate and established pain responses discussed in the previous sections

one whereby the tural and fu reorganization of the nervous system and alters the final adult patshytern of connections

It is commonly thought that the infant nervous system has greater powers of recovshyery than that of the adult However in many cases developing neural processes require particular conditions at critical times in order to develop normally (42) An example of this is the dependence on trophic support of senshysory neurons provided by peripheral target tissues during development If a cutaneous sensory axon is damaged during a critical stage of development this essential support will be cut off and result in irreversible death of the dorsal root ganglion cells (43 44) The trophic support is provided at least in part by nerve growth factor (NGF) which is proshyduced in target tissues and transported back to the cell bodies The cell death resulting from axotomy can be prevented by exogeshynous NGF administration (43) This is not only true of peripheral sensory ganglion cells motoneurons and central cells in the spinal cord and brain die if their axons are cu t off from their targets during develop shyment Furthermore the consequences of axshyonal damage to even a small perip h ra I nerve during developmen t are far-reaching go ing beyond th death of its own cell bod -

ies The death of these peripheral neurons leaves an area of deafferentation in the spishynal cord This causes severe retardation of postsynaptic growth and the somadendritic development of second order spinal-cord cells is virtually arrested (45) Furthermore nearby intact sensory neurons send collatshyeral sprouts considerable distances into the deafferented area of the cord and form synshyaptic connections within the region (4647) This means that now totally inappropriate cord regions normally devoted to inputs from the damaged area are processing inshyformation from nearby undamaged skin In other words the nearby skin areas have a greater than normal representation in the CNS This reorganization is also observed in the trigeminal regions following facial injushyries (48) The effects are not restricted to the first synapse either but continue on up through the CNS Peripheral nerve injury in the neonate alters connections in the thalashymus and the somatosensQry ltQrtex (49 20)

the body surface or somatotopic map in the brain Secondary transneuronal degenerashytion even of the corticospinal tract (CST) has been induced after nerve section in newborn rats (51)

These longterm consequences of injury in laboratory rats are not simply eady embryshyological events of interest to developmental biologists but have important implications in human premature and full-term infants who undergo painful experiences For exshyample traumatic interventions of the kind that are necessarily undertaken in neonatal intensive-care wards may well cause a simishylar reorganization in the somatosensory and motor systems as are seen in the rat model While ~e are discovering the nature of the new functional connections that can be formed in the rat we still remain ignorant of what if any sensory disturbances such reshyorganization may cause in human infants Obviously more research both in the laboshyratory and clinical setting is needed to furshyther expand our knowledge in this area

APPLIED PHYSIOLOGY OF PAIN The previous sections describe experimental studies of the developmental neuroanatomy and neurophysiology of th e pain system deshytailing the effects of nociceptive stimuli in