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Stress‐induced analgesia in mice: evidence for interaction between endocannabinoids and cholecystokinin
Author(s) -
Kurrikoff Kaido,
Inno Jan,
Matsui Toshimitsu,
Vasar Eero
Publication year - 2008
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2008.06160.x
Subject(s) - cholecystokinin , endocannabinoid system , neuroscience , psychology , pharmacology , oxytocin , chemistry , medicine , receptor
Stress‐induced analgesia (SIA) is an important endogenous mechanism in response to stressful stimuli. Opioid peptides, as well as endocannabinoids, are known mediators of SIA. We were interested in whether the endocannabinoid tone and the resulting SIA could be influenced by changing the activity of cholecystokinin (CCK) in mice. This hypothesis is related to recent evidence showing a cellular colocalization of neuropeptide CCK and cannabinoid type 1 (CB 1 ) receptors in many central nervous system structures. However, the physiological relevance of this colocalization is unknown. Our aim was to test whether abolishing the endogenous CCK tone might influence the cannabinoid‐mediated form of SIA. As expected, the CB 1 antagonist rimonabant prevented the development of analgesia in response to footshock‐induced stress in wild‐type mice. In contrast, CCK type 2 (CCK 2 ) receptor‐deficient mice developed SIA regardless of rimonabant treatment. Naloxone, an opioid antagonist, antagonized SIA in both wild‐type and CCK 2 receptor‐deficient homozygous mice. This finding suggests that CCK, through CCK 2 receptors, modulates the action of endocannabinoids. Gene expression analysis revealed an up‐regulation of CCK 2 receptor gene in the lumbar spinal cord and mesolimbic area in wild‐type mice in response to stress. In addition, wild‐type mice displayed up‐regulation of genes implicated in endocannabinoid‐mediated neurotransmission (elevation of CB 1 receptor, 2‐arachidonoylglycerol and the anandamide‐synthesizing enzymes sn‐1‐diacylglycerol lipase alpha and N ‐acyl‐phosphatidylethanolamine‐hydrolysing phospholipase D) in response to stress in the lumbar spinal cord and mesolimbic area. We did not find any of these changes in CCK 2 receptor‐deficient homozygous mice. Altogether, behavioural and gene expression studies reflect an involvement of CCK 2 receptors in the development of endocannabinoid‐mediated SIA.