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.
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Acknowledgments
We would like to thank Dr. Roger Pertwee, University of Aberdeen, for helpful discussions about the data presented in the manuscript. KLW was supported by a CGS Scholarship from NSERC. The research was supported by research grants to LAP from NSERC (92057) and to A. Makriyannis from NIH.
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Wills, K.L., Vemuri, K., Kalmar, A. et al. CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats. Psychopharmacology 231, 4291–4300 (2014). https://doi.org/10.1007/s00213-014-3575-5
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DOI: https://doi.org/10.1007/s00213-014-3575-5