Premium
Tolerance and cross‐tolerance among high‐efficacy synthetic cannabinoids JWH‐018 and JWH‐073 and low‐efficacy phytocannabinoid Δ 9 ‐THC
Author(s) -
Fantegrossi William E,
Franks Lirit N,
Vasiljevik Tamara,
Prather Paul L
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1097.1
Subject(s) - pharmacology , cannabinoid , cannabinoid receptor , drug tolerance , medicine , abstinence , cross tolerance , synthetic cannabinoids , delta 9 tetrahydrocannabinol , receptor , agonist , morphine , psychiatry
Repeated administration of cannabinoid agonists has been shown to result in tolerance to several central and peripheral effects in laboratory animals, and to cellular effects observed in vitro. Intrinsic efficacy is known to modulate pharmacodynamic tolerance at several central receptor systems, but whether this phenomenon also applies to cannabinoid receptors has not been adequately explored. In these studies, daily injections of the high‐efficacy synthetic cannabinoids JWH‐018 and JWH‐073, or the low‐efficacy phytocannabinoid Δ 9 ‐THC were administered to mice previously prepared with radiotelemetry probes capable of simultaneously monitoring core temperature and locomotor activity. In separate groups of mice, the effects of JWH‐018 and JWH‐073 were assessed in subjects with or without a history of Δ 9 ‐ THC administration. Repeated administration of all three cannabinoids resulted in almost complete tolerance to hypothermic effects within 5 days, and when re‐challenged with the same dose after a 14‐day drug abstinence period, some degree of tolerance was still evident for all three cannabinoids. Interestingly, no tolerance to locomotor suppression was noted for any of the cannabinoids. Mice made tolerant to the hypothermic effects of Δ 9 ‐ THC after 4 daily administrations also exhibited near complete tolerance to the hypothermic effects of JWH‐018 and JWH‐073 on day 5, and in both cases, residual tolerance was still apparent after a 14‐day drug abstinence period. Potential mechanisms for these observed in vivo effects were investigated in vitro using assays of CB1 receptor expression and function. These studies suggest that intrinsic efficacy at CB1 receptors is not a primary variable in eliciting tolerance to hypothermic effects in mice. This work supported by RR020146 and RR029884.