CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats
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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.
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- Authors
- Wills, K. L., Vemuri, K., Kalmar, A., Lee, A., Limebeer, C. L., Makriyannis, A., & Parker, L. A.
- Affiliations
- University of Guelph (CA)
- Northeastern University (US)
- Corresponding author
- Parker, Linda A.
- Venue
- Psychopharmacology
- Published
- 2014-04-27
- Volume
- 231
- Issue
- 22
- Pages
- 4291-4300
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC4209202
- OpenAlex
- W2117033028
- Cited by
- 29
- References
- 62
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 1
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-07-31)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- National Institute on Drug Abuse (R01DA003801, R37DA023142, R01DA031020)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- CB1 receptor antagonism, morphine withdrawal, naloxone-precipitated withdrawal, conditioned place aversion, endocannabinoid system, fatty acid amide hydrolase inhibitors, URB597, AM251, reinstatement, opioid withdrawal
- MeSH terms
- Affect, Analgesics, Opioid, Animals, Male, Morphine, Naloxone, Narcotic Antagonists, Substance Withdrawal Syndrome, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Rats
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