Review article Cholecystokinin and endogenous opioid peptides: Interactive influence on pain, cognition, and emotion Andrea L.O. Hebb a, * , Jean-Franc ¸ois Poulin b , Sean P. Roach a , Robert M. Zacharko c , Guy Drolet b a Dalhousie University, Department of Pharmacology, Faculty of Medicine, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS, Canada B3H 1X5 b Centre de Recherche du CHUL (CHUQ), Neurosciences, Universite ´ Laval, Que ´bec, QC, Canada c Institute of Neuroscience, Carleton University, ON, Ontario, Canada Accepted 26 August 2005 Available online 20 October 2005 Abstract It is well documented that stressful life experiences contribute to the etiology of human mood disorders. Cholecystokinin (CCK) is a neuropeptide found in high concentrations throughout the central nervous system, where it is involved in numerous physiological functions. A role for CCK in the induction and persistence of anxiety and major depression appears to be conspicuous. While increased CCK has been associated with motivational loss, anxiety and panic attacks, an increase in mesocorticolimbic opioid availability has been associated with coping and mood elevation. The close neuroanatomical distribution of CCK with opioid peptides in the limbic system suggests that there may be an opioid-CCK link in the modulation and expression of anxiety or stressor-related behaviors. In effect, while CCK induces relatively protracted behavioral disturbances in both animal and human subjects following stressor applications, opioid receptor activation may change the course of psychopathology. The antagonistic interaction of CCK and opioid peptides is evident in psychological disturbances as well as stress-induced analgesia. There appears to be an intricate balance between the memory-enhancing and anxiety-provoking effects of CCK on one hand, and the amnesic and anxiolytic effects of opioid peptides on the other hand. Potential anxiogenic and mnemonic influences of site-specific mesocorticolimbic CCK and opioid peptide availability, the relative contributions of specific CCK and opioid receptors, as well as the time course underlying neuronal substrates of long-term behavioral disturbances as a result of stressor manipulations, are discussed. D 2005 Elsevier Inc. All rights reserved. Keywords: Anxiety; Depression; Learning; Memory; Opioid; Pain; Stress Contents 1. Introduction ............................................................. 1226 2. Stress-induced alteration in endogenous opioid peptides and CCK: implications for anxiety ................... 1226 3. Evidence for CCK and endogenous opioid peptide interactions in the modulation of anxiety and cognitive change ....... 1227 4. Consideration of A-y/CCK B receptor interactions and encoding of salient environmental experiences ............... 1227 5. Endogenous opioid peptide and CCK interactions: stress-induced analgesia and pain ....................... 1229 6. Endogenous opioid peptides and CCK interactions: depression .................................. 1230 7. Endogenous opioid peptides and CCK interactions: learning and memory ............................. 1231 8. Conclusions ............................................................. 1232 References ................................................................ 1232 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.08.008 Abbreviations: BLA, basolateral nucleus of the amygdala; CEA, central amygdaloid nucleus; CCK, cholecystokinin; CNS, central nervous system; CREB, cAMP-response-element-binding protein; CREM/ICER, cAMP-responsive modulatory inducible cAMP early repressor; CSM, conditioned suppression of motility; DALA, D-Ala2-Met5-enkephalinamide; ENK, enkephalin; LD, light dark test; TMT, trimethylthiazoline; VTA, ventral tegmental area. * Corresponding author. Tel.: +1 902 494 6232; fax: +1 902 494 6294. E-mail address: alohebb@dal.ca (A.L.O. Hebb). Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 1225 – 1238 www.elsevier.com/locate/pnpbp