Biobehavioral Reviews, Vol. 1, pp. 137-- 139, 1977. Copyright © ANKHO International Inc. All rights of reproduction in any form reserved. Printed in the U.S.A.

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Psychological or Physiological Analgesics: A Reconciliation

GEORGE SINGER

Department o f Psychology, La Trobe University, Bundoora, Australia 3083

(Received 14 June 1977)

SINGER, G. Psychological or physiological analgesics: A reconciliation. BIOBEHAV. REV. 1(2) 137-139, 1977. - Recently opiate receptors have been discovered in the central nervous system (CNS) which show specificity for opiate drugs as well as for a range of endogenous polypeptides. These endogenous opiates are released during stress and under those conditions have analgesic properties, also their peripheral injection leads to analgesia. In the present paper a common biochemical substrate which involves these polypeptides as an explanation of pharmacological and psychological analgesics is proposed. The evidence for this thesis is reviewed and further experimental tests are suggested.

Opiate receptors Central nervous system Endogenous polypeptides

ANALGESIC methods which do not involve drugs are usually referred to as psychological or centrally operative analgesics. They include placebo treatments [9], hypnosis [16], acupuncture [19], distracting stimulation [13], (including other painful stimuli), behavior modification [12] and cognitive control [23]. These methods have been widely studied in the laboratory and have also been used in clinical settings. Pain reduction resulting from these methods is regarded as nonsensory and a form of mind- body dualism is implicit in this dichotomy. This is not necessarily a naive mind-body dualism of the Descartes type but a belief that different systems or structures are involved in psychological and physiological processes although they are both based in the central nervous system.

Recent experiments on acupuncture [7] and placebo reactions to pain [10] in which the signal-detection method was used, make a distinction between sensory and other nonsensory factors in the perception of pain which, although it is strictly operational, may still parallel the more speculative dualist distinctions made earlier. Melzack and Wall [25] who have proposed a theory which involves the balancing of excitatory and inhibitory pain stimuli through a gating mechanism, have recently added moti- vational and central cognitive pathways to their model in order to cope with the well known psychological analgesic methods [24]. Although ascending excitatory and de- scending inhibitory neurons have been shown to be activated following nociceptive stimulation, Melzack's model fails to explain the mechanisms which trigger off central inhibition. A further factor which adds to the puzzle of psychological analgesics is that certain centrally

acting anti-anxiety or anti-depressant drugs [11] have analgesic effects and there is a widespread belief that even the powerful pain killing effect of narcotic drugs is through their action on a central mechanism and not through peripheral sensitivity reduction [ 17].

Recently, opiate receptors have been discovered in the brain which show specificity for opiate drugs and are blocked by opiate blockers [27,28]. Also a range of endogenous opiates have been found in the CNS which are capable of stimulating the opiate receptors, these are the enkephalins and endorphins. Initially, it was found that these compounds had only short term analgesic effects when injected directly into brain tissue [4,30] and no analgesic effects were observed with peripheral injections of these endogenous polypeptides. The short term effects of intercerebral injections were probably the result of rapid enzymatic action on these compounds in vivo. More recent reports indicate that a series of D-amino acid substitute analogs of the opiate peptide not only compete with tritiated enkephalins for opiate receptors but also show more prolonged analgesic activity [26]. The most interesting report on the relationships between enkephalins and analgesia is by Akil et al. [ 1 ] who showed that acute intermittent inescapable foot shock for a period of 30 or 60 min induced a significant rise in endogenous opiates which was apparent immediately and lasted for 15 min. Con- comitant to this stress induced rise in opiate levels, there was a significant analgesic effect as indexed by an increase in latency of the tail-flick response. This analgesic effect was more persistent for the 60 min group since it remained significant for 2 hr after stress. Naloxone, an opiate

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antagonist, altered the pattern of responsiveness with analgesia being completely reversed within six trials and the animals becoming significantly hyperalgesic in later trials.

These experimental findings may provide an explanation of the frequently quoted casual observations by Beecher [3], that severely wounded soldiers who had been through battle stress reported much less pain than similarly wounded persons would do under more normal cir- cumstances, e.g. in hospital wards. This was ascribed to anxiety relief being a distracting stimulus but it may well be a result of poststress enkephalin induced analgesia similar to that reported by Akil et al. [ 1 ].

In the present paper, the possibility of a common central mechanism for both psychological and physiological anal- gesics based on endogenous opiate release is proposed. The endogenous neuropeptides provide a neural substrate which may be able to trigger off inhibitory stimulation in descending neural pathways and block or reduce the central input from peripheral stimulation which is transmitted through ascending fibres. This would inhibit pain per- ception for variable intervals. So far it has been shown that these neuropeptides are released when an animal is stressed, that they have analgesic properties when thus released or when injected peripherally or centrally into the organism. Further evidence suggests that they show cross tolerance with synthetic narcotic analgesics which in turn shows cross tolerance with stimulation produced analgesia [21]. The neuropeptides are also involved in other behaviors which may be components in psychological analgesia, such as production of prolonged muscular rigidity and immobility [6], attention and learning [19]. Furthermore, their analgesic action is reversed by the morphine antagonist naloxone [2]. There are thus a number of parallels between the various analgesic methods. It remains to be shown how and when these neuropeptides are released. There are two types of experimental approaches to test the thesis which has been put forward in this paper. Firstly, the use of animal subjects employing psychological analgesics derived from human studies, the dependent variables being both changes in pain threshold and neuropeptide levels. Some methods which seem applicable in the animal laboratory are distracting stimulation (including pain stimulus), acu- puncture and possibly learning to perform responses which are competing with the pain test response. Secondly, studies on humans where neuropeptide levels can be monitored during the application of psychological anal- gesics, this most direct method may have to await advances in technology of measuring peptides in vivo. Other human studies which may be more feasible at the moment are the interaction effect of psychological analgesics and the administration of stable neuropeptides and their antagonists on pain thresholds and studies of these interactions on acute or chronic narcotic addicts. Testable predictions can be made about changes in pain threshold during addiction and withdrawal phases, if both pain perception and narcotic addiction are based on activity of the same biochemical systems.

It has already been shown that acupuncture analgesia in humans is reversed by naloxone and not by saline injections and that naloxone had no effect on baseline pain thresholds which suggests the involvement of an opiate system [20]. These findings were not confirmed in another study of acupuncture. In contrast naloxone had no antagonistic effect on hypnotically induced analgesia in humans, which may be due to the complex factors involved in hypnosis

generally [15]. These negative findings led the ex- perimenters to the rejection of the hypothesis, similar to the one proposed in this paper, that hypnotic analgesia is mediated through opiate receptors. In fact analgesic endo- genous opiate release may depend on stress factors as shown in Akil's [1] experiment and laboratory pain may have to have more realistic stress or anxiety components before psychologic analgesics can operate via the opiate substrate. It has also been suggested that the morphine like factor is released only under special circumstances [8]. In fact, the necessity for stress factors or other special circumstances may be the reason for recent disenchantment with the use of the experimental method as a predictor for clinically applicable analgesics.

In a recent review of behavioral, anatomical, physio- logical and pharmacological studies of analgesic methods, Mayer and Price [22] point out the similarity between stimulation and opiate produced analgesia. This is based on studies of naloxone blocking of both stimulation and opiate produced analgesia and also on cross tolerance mentioned earlier. They provide convincing evidence of the similarity between these two analgesia and the likelihood of a common substrate which involves the endogenous opiates as well as catecholaminergic and serotonergic transmitters. They further argue a convincing case that these analgesics involve both ascending activating systems as well as decending inhibitory systems.

Mayer and Price [22] suggest that stress produced analgesia which is not reduced by naloxone nor by bilateral lesions of the dorsolateral funiculus is subserved by different central mechanisms and that other analgesics may also be subserved by these other systems. However the evidence by Akil et al. [1] that endogenous opiates or levels are increased during stress and that this leads to tail-flick analgesia supports the thesis for a common substrate proposed in the present paper.

The thesis proposed in this paper on the role of the endogenous peptides as the modulator of neural inhibition in pain may not only explain the basis of psychological analgesias but may also be useful in the explanation of some pains arising without activation of peripheral systems. It has been suggested that pains which are relieved by anti-convulsants may arise from injury of the nervous system and that this injury predominantly affects large diameter fibres [ 11 ]. It therefore interferes with inhibitory modulation and spontaneous firing in small fibres which continue unrestricted, thereby giving rise to pain sensations. An alternative to injury of the descending neural pathways is some abnormality in the neuropeptide metabolism which reduces the activity in these pathways and may have a similar effect such as the disruption of normal inhibitory control mechanisms.

The case for the greater generality of the role of neuropeptides in analgesia is further strengthened by two recent findings. The first is that pain thresholds in mice which are lowered by nitrous oxide are blocked by naloxone and naltrexone which are both narcotic antag- onists and that the analgesic effect of nitrous oxide is abolished by four days pretreatment with morphine [5]. Since the mode of action of nitrous oxide is different from that of narcotics a common substrate for analgesia such as is provided by endogenous neuropeptides, is a plausible explanation for these data. The second finding is the isolation of a morphine like factor from human cerebro spinal fluid drawn from the lumbar region or from the

AN A N A L G E S I C R E C O N C I L I A T I O N 139

vent r ic le of pa t i en t s in a neurosurg ica l cl inic and the obse rva t ion t ha t p a t i e n t s w i th t r igemina l neura lgia seem to have lower levels of ML F t h a n pa t i en t s w i th o t h e r diagnoses [ 2 9 ] . The researchers suggest t ha t a causal r e la t ionsh ip m a y exist b u t add the cau t ion t h a t the n u m b e r of cases in the i r s tudy was very small to arrive at a def ini t ive conc lus ion .

A l t h o u g h there are a n u m b e r of missing l inks in the thesis p roposed in th is paper , it p rov ides the basis for the

r e so lu t ion of the pain or analgesia pa radox . Some of the negat ive f indings so far [ 8, 14, 15 ] shou ld n o t be regarded as d iscouraging since they may be resolved w h e n the c o n d i t i o n s of release of n e u r o p e p t i d e s have been more fully explored . F u r t h e r progress requi res b o t h clinical and e x p e r i m e n t a l s tudies in th is area, p re fe rab ly guided by the p resen t hypo thes i s .

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2. Akil, H., D. J. Mayer and J. C. Liebeskind. Antagonism of stimulation-produced analgesia by naloxone, a narcotic antag- onist. Science 191: 961-962, 1976.

3. Beecher, H. K. Measurement o f Subjective Responses. New York: Oxford University Press, 1959.

4. Belluzzi, J. D., N. Grant, V. Garsky, D. Sarantakis, C. D. Wise and L. Stein. Analagesia induced in vivo by central adminis- tration of enkephalin in rat. Nature 260: 625-625 , 1976.

5. Berkowitz, B. A., S. H. Ngai and A. D. Fink. Nitrous oxide "analgesia" resemblance to opiate action. Science 194: 967-968, 1976.

6. Bloom, F., D. Segal, N. Ling and R. Guillemin. Endorphins: Profound behavioural effects in rats suggest new etiological factors in mental illness. Science 194: 630-632 , 1976.

7. Clark, W. C. and J. C. Yang. Acupunctural analgesia? Eval- uation by signal detection theory. Science 184: 1096-1098, 1974.

8. E1-Sobky, A., J. O. Dostrovsky and P. D. Wall. Lack of effect of naloxone on pain perception in humans. Nature 263: 783-784, 1976.

9. Evans, F. J. The placebo response in pain reduction. Adv. Neurol. 4: 289-296, 1974.

10. Feather, B. W., C. R. Chapman and S. B. Fisher. The effect of a placebo on the perception of painful radiant heat stimuli. Psychosom. Med. 34: 290-294, 1972.

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15. Goldstein, A., and E. R. Hilgard. Failure of the opiate antagonist naloxone to modify hypnotic analgesia. Proc. natn. Acad. ScL 72: 2041-2043, 1975.

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18. Kastin, A. J., E. L. Scollan, M. G. King, A. V. Schally and D. H. Coy. Enkephalin and a potent analog facilitate maze performance after intraperitoneal administration in rats. Pharmac. Biochem. Behav. 5: 691-696 , 1976.

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