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CB1 Antagonism: Interference With Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats

CB1 Antagonism: Interference With Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats

Kiri L Wills, Kiran Vemuri, Alana Kalmar, Alan Lee, Cheryl L Limebeer, Alexandros Makriyannis, Linda A Parker

Psychopharmacology (Berl). 2014 Nov;231(22):4291-300.

PMID: 24770676

Abstract:

Rationale:
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.
Materials and 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP614726851	AM4113		614726-85-1	Price

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