CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats.
BACKGROUND
Modulation of the endocannabinoid system has been found to interfere with opiate withdrawal. The potential of activation and blockade of the endocannabinoid system to prevent the aversive-affective state of naloxone-precipitated morphine withdrawal (MWD) was investigated in a one-trial conditioned place aversion (CPA) paradigm.


OBJECTIVE
CPA provides a sensitive measure of the motivational effects of acute MWD. The potential of the fatty acid amide hydrolase (FAAH) inhibitors, URB597 and PF-3845, the CB1 antagonist/inverse agonist, AM251, and the neutral CB1 antagonists, AM4113 and AM6527 (oral), to interfere with establishment of a MWD-induced CPA was investigated. As well, the potential of AM251 and AM4113 to interfere with reinstatement of a previously established MWD-induced CPA was investigated.


METHODS
Using a one-trial place conditioning paradigm, rats were administered naloxone (1 mg/kg, subcutaneous (s.c.)) 24 h after receiving a high dose of morphine (20 mg/kg, s.c.) and were placed on the conditioning floor. To determine the effect of each pretreatment drug on the establishment of the MWD-induced CPA, URB597 (0.3 mg/kg, intraperitoneally (i.p.)), PF-3845 (10 mg/kg, i.p.), AM251 (1 or 2.5 mg/kg, i.p.), AM4113 (1 or 2.5 mg/kg, i.p.), and AM6527 (5 mg/kg, oral) were administered prior to conditioning.


RESULTS
AM251 (2.5, but not 1 mg/k), AM4113, and AM6527, but not URB597 or PF-3845, interfered with the establishment of the MWD-induced CPA. AM251 and AM4113 did not prevent reinstatement of the CPA.


CONCLUSIONS
Neutral antagonism of the CB1 receptor reduces the aversive affective properties of morphine withdrawal.
Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G 2W1, Canada.
Kiri L
KL
Wills
Kiran
K
Vemuri
Alana
A
Kalmar
Alan
A
Lee
Cheryl L
CL
Limebeer
Alexandros
A
Makriyannis
Linda A
LA
Parker
D000339:Affect / Q000187:drug effects; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D043884:Receptor, Cannabinoid, CB1; D009270:Naloxone; D009020:Morphine