ThePeriaqueductalGray(PAG)€¦ · 1 (CB1) agonists or drugs that facilitate eCB-mediated neurotransmission produce antinociceptive and antiaversive eﬀects. Stimulated by these

Hindawi Publishing CorporationNeural PlasticityVolume 2009, Article ID 360907, 2 pagesdoi:10.1155/2009/360907

EditorialThe Periaqueductal Gray (PAG)

T. A. Lovick1 and Robert Adamec2

1 College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK2 Department of Psychology, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada A1B 3X9

Correspondence should be addressed to Robert Adamec, [email protected]

Received 21 January 2009; Accepted 21 January 2009

Copyright © 2009 T. A. Lovick and R. Adamec. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

This issue covers a broad territory of PAG function: neu-ropharmacology, functional organization, and PAG plasticityin adaptive behavior, emotion, anxiety, and the less-studiedplasticity of the PAG function in females.

Interest in the involvement of PAG in defensive behaviorhas a long history. Thinking about this area was radicallychanged by the seminal contributions of Bandler andDePaulis in defining functional columns arranged in bothcoronal and saggital planes of the PAG. Most papers inthis section respect the importance of those functionalcolumns while adding to our understanding how they mightcontribute to panic, anxiety, defensive response to naturalthreats, as well as aversive learning.

Del-Ben and Graeff in the paper entitled “Panic dis-order: Is the PAG involved?” review preclinical as wellas human imaging research in the contribution of PAGdysfunction to panic anxiety disorder. Others have shownhow preclinical models of posttraumatic stress disorder(PTSD) and using brief exposure to predators (predatorstress) have helped to advance our understanding of theneural substrates of stress-induced lasting sensitization ofrodent anxiety including potentiation of startle response.Adamec et al. contribution in the paper entitled “Viral VectorInduction of CREB Expression in the Periaqueductal GrayInduces a Predator Stress-Like Pattern of Changes in pCREBExpression, Neuroplasticity and Anxiety in Rodents” extendsinitial findings implicating pCREB expression in the lateralcolumn of the PAG in neuroplastic changes in amygdala-PAGcommunication as mediators of predator stress-enhancedstartle and anxiety. Using viral vector enhancement of CREBexpression in the PAG, the authors provide support for theidea that stress-precipitated increases in pCREB in the PAGare sufficient to potentiate central amygdala to PAG neuraltransmission, to increase anxiety in the elevated plus maze,and to potentiate startle response. In a related vein, exposure

to stressful stimuli increases endocannabinoid (eCB) levelsin the PAG and local administration of cannabinoid receptor1 (CB1) agonists or drugs that facilitate eCB-mediatedneurotransmission produce antinociceptive and antiaversiveeffects. Stimulated by these findings, Moreira et al. in“Anti-aversive effects of cannabinoids: is the periaqueductalgray involved?” explore the anxiolytic potential of PAGinjection of CB1 agonists and cannabidiol in a variety oftests of anxiety as well as in contextual fear conditioning.They provide evidence that dorsal lateral PAG is a site ofantiaversive actions of cannabinoids. Other PAG columnarfunction (ventrolateral PAG-VlPAG) in antinociception isexplored by Morgan et al. in “Behavioral Consequencesof Delta Opioid Receptor Activation in the Periaqueduc-tal Gray of Morphine Tolerant Rats”. It is known thatchronic morphine administration shifts delta-opioid recep-tors (DOR) from the cytoplasm to the plasma membrane.Moreover, microinjection of morphine into the VlPAGproduces antinociception. In light of these findings, it washypothesized that movement of DORs to the membranewould induce antinociception to the DOR agonist deltorphinII as a way to compensate for morphine tolerance. Theirfindings suggest that chronic morphine administration altersDORs in the vlPAG with little evidence of compensationfor the decrease in antinociception caused by morphinetolerance.

PAG Function in Females. Until very recently, research onthe PAG along with most other brain areas was conductedalmost exclusively in males with the implicit assumption thatthe anatomy and physiology were the same in females. Threearticles in this issue show that this is not the case. Not only arethere significant differences in the organization of the PAGbetween the sexes but the circuitry of the female PAG alsoexhibits considerable plasticity in response to changes in itshormonal milieu.

2 Neural Plasticity

Lloyd and Murphy in the paper entitled “The Roleof the Periaqueductal Gray in the Modulation of Pain inMales and Females: Is the Anatomy and Physiology ReallyThat Different?” show that descending projections from thePAG, which are believed to modulate spinal processing ofnociceptive input, are more numerous in female rats thanin males. Paradoxically morphine, which exerts much ofits antinociceptive effects by activating these projections,excited a much smaller proportion of the neurones infemales compared to males, a finding that may explain theclinical finding of reduced efficacy of the analgesic effects ofmorphine in women compared to men. Lovick and Devallin the paper entitled “The Role of the Periaqueductal Gray inthe Modulation of Pain in Males and Females: Is the Anatomyand Physiology Really That Different?” show how the fall inproduction of progesterone during the late dioestrus phase ofthe oestrous cycle leads to upregulation of certain subunitsof the GABAA receptor in the PAG. One of the functionalconsequences is a decrease in ongoing GABAergic tone andan increase in neural excitability within PAG circuits. Thesechanges may underlie the increased susceptibility to thedevelopment of stress-induced hyperalgesia that was shownto occur during late dioestrus and may also be relevant toLloyd and Murphy’s reports of a reduction in morphine’s effi-cacy in female rats during dioestrus. Mota-Ortiz et al. in thepaper entitled “Afferent Connections to the Rostrolateral Partof the Periaqueductal Gray: a Critical Region Influencingthe Motivation Drive to Hunt and Forage” examine afferentinputs to the rostrolateral PAG (rlPAG ) in female rats. Innursing females, morphine treatment induces a behavioral“switch” from maternal to foraging behavior which is medi-ated via the rostrolateral PAG (rlPAG ). The authors reportthat the rlPAG receives inputs from medial prefrontal corticalareas involved in controlling attention-related and decision-making processes. Other afferents from different amygdalar,hypothalamic, and brainstem sites provide information toPAG related to feeding, drinking, or hunting behaviors.It is suggested that this unique combination of afferentconnections positions the rlPAG to influence the decisionwhether hunting/foraging or other behaviors would be themost appropriate adaptive response for females, particularlyin the presence of their young.

These papers are by no means exhaustive of the interestand breadth of work in the PAG field. Nevertheless, togetherthey reflect the rich functional diversity of activities ofthe PAG. Moreover, they make apparent the importanceof paying attention to sex and particular columnar areaswhen studying this fascinating structure, whose activity is offundamental importance for survival of the individual in achallenging and constantly changing environment.

T. A. LovickRobert Adamec

Submit your manuscripts athttp://www.hindawi.com

Epilepsy Research and TreatmentHindawi Publishing Corporationhttp://www.hindawi.com Volume 2013

Hindawi Publishing Corporation http://www.hindawi.com Volume 2013Hindawi Publishing Corporation http://www.hindawi.com Volume 2013

The Scientific World Journal

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2013

Research and TreatmentAutism


Neurodegenerative Diseases

Journal of


Computational and Mathematical Methods in Medicine


Neurology Research International


Depression Research and Treatment

Alzheimer’s DiseaseInternational Journal of

Hindawi Publishing Corporation http://www.hindawi.com Volume 2013


Cardiovascular Psychiatryand Neurology


Neural Plasticity

Stroke Research and Treatment


BioMed Research International


Parkinson’s Disease



Psychiatry Journal

ScientificaHindawi Publishing Corporationhttp://www.hindawi.com Volume 2013


Sleep Disorders


Brain ScienceInternational Journal of


Neuroscience Journal


Research and TreatmentSchizophrenia

Documents

ThePeriaqueductalGray(PAG)€¦ · 1 (CB1) agonists or drugs that facilitate eCB-mediated neurotransmission produce antinociceptive and antiaversive eﬀects. Stimulated by these