CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats

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 (sc)) 24 h after receiving a high dose of morphine (20 mg/kg, sc) 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 (ip)), PF-3845 (10 mg/kg, ip), AM251 (1 or 2.5 mg/kg, ip), AM4113 (1 or 2.5 mg/kg, ip), 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.

Double Dissociation of Monoacylglycerol Lipase Inhibition and CB1 Antagonism in the Central Amygdala, Basolateral Amygdala, and the Interoceptive Insular Cortex on the Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats

“…Subjects were male Sprague-Dawley rats weighing between 350 and 450 g. Animals were housed individually as described in Wills et al (2014). All animal procedures were approved by the Animal Care Committee of the University of Guelph and adhere to the guidelines of the Canadian Council of Animal Care.…”

“…Morphine, naloxone, and vehicle (VEH) were prepared as previously described in Wills et al (2014). For the systemic experiments (experiments 1 and 2), the MAGL inhibitor, MJN110, and CB 1 antagonist, AM251, were prepared in VEH at a final concentration of 10 mg ml − 1 and 1 mg ml − 1 , respectively.…”

“…For the systemic experiments (experiments 1 and 2), the MAGL inhibitor, MJN110, and CB 1 antagonist, AM251, were prepared in VEH at a final concentration of 10 mg ml − 1 and 1 mg ml − 1 , respectively. The concentration of MJN110 was selected on the basis of its ability to maximally inhibit MAGL activity in rats in vivo , whereas the concentration of AM251 has been previously found to have no effect on the establishment of a naloxone-precipitated CPA (Wills et al, 2014). For the intracranial experiments (experiments 3 and 4), MJN110 and AM251 were prepared in the same VEH at a concentration of 5 and 0.25 μg/μl, respectively; for experiment 5, MJN110 and AM251 were prepared in the same VEH at a concentration of 2 and 0.1 μg/μl, respectively.…”

“…The eCB system consists of two receptors (CB 1 and CB 2 ), the eCBs, anandamide (AEA; Devane et al, 1992) and 2-arachidonyl glycerol (2-AG; Sugiura et al, 1995) and the enzymes that regulate their synthesis and degradation (Ahn et al, 2008). CB 1 antagonism interferes with a naloxone-precipitated MWD CPA (Wills et al, 2014) and with somatic symptoms of MWD in rats (Mas-Nieto et al, 2001;Rubino et al, 2000). However, somewhat paradoxically THC (Bhargava, 1976), AEA (Vela et al, 1995), and 2-AG (Yamaguchi et al, 2001) have also been reported to reduce the intensity of MWD somatic symptoms in mice.…”

“…Ramesh et al (2011) reported that both FAAH and MAGL (JZL184) inhibitors were effective in attenuating precipitated MWD somatic symptoms in mice; although the MAGL inhibitor was more effective than was the FAAH inhibitor. Although FAAH inhibition does not significantly modify the establishment of a naloxone-precipitated MWD CPA (Wills et al, 2014), the potential of MAGL inhibition to interfere with the affective component of acute naloxoneprecipitated MWD has not been evaluated in rats. Recently, a potent and selective MAGL inhibitor, MJN110 , has been developed that selectively elevates 2-AG by 10-fold, but not AEA.…”