Abstract
Rationale
Tolerance to cannabinoids could limit their therapeutic potential. Male mice expressing a desensitization-resistant form (S426A/S430A) of the type-1 cannabinoid receptor (CB1R) show delayed tolerance to delta-9-tetrahydrocannabinol (∆9-THC) but not CP55,940. With more women than men using medical cannabis for pain relief, it is essential to understand sex differences in cannabinoid antinociception, hypothermia, and resultant tolerance.
Objective
Our objective was to determine whether female mice rely on the same molecular mechanisms for tolerance to the antinociceptive and/or hypothermic effects of cannabinoids that we have previously reported in males. We determined whether the S426A/S430A mutation differentially disrupts antinociceptive and/or hypothermic tolerance to CP55,940 and/or Δ9-THC in male and female S426A/S430A mutant and wild-type littermates.
Results
The S426A/S430A mutation conferred an enhanced antinociceptive response for ∆9-THC and CP55,940 in both male and female mice. While the S426A/S430A mutation conferred partial resistance to ∆9-THC tolerance in male mice, disruption of CB1R desensitization had no effect on tolerance to ∆9-THC in female mice. The mutation did not alter tolerance to the hypothermic effects of ∆9-THC or CP55,940 in either sex. Interestingly, female mice were markedly less sensitive to the antinociceptive effects of 30 mg/kg ∆9-THC and 0.3 mg/kg CP55,940 compared with male mice.
Conclusions
Our results suggest that disruption of the GRK/βarrestin2 pathway of desensitization alters tolerance to Δ9-THC but not CP55,940 in male but not female mice. As tolerance to Δ9-THC appears to develop differently in males and females, sex should be considered when assessing the therapeutic potential and dependence liability of cannabinoids.
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Abbreviations
- 2-AG:
-
2-Arachidonoylglycerol
- ACEA:
-
Arachidonyl-2-chloroethylamide
- AEA:
-
Anandamide
- ANOVA:
-
Analyses of variance
- βArr2:
-
Beta-arrestin 2
- %∆BT:
-
Percent change in body temperature
- CB:
-
Cannabinoid
- CB1/CB1R:
-
Type-1 cannabinoid receptor
- CB2/CB2R:
-
Type-2 cannabinoid receptor
- CB1A:
-
SR141716A (CB1R antagonist)
- CB2A:
-
SR144528 (CB2 inverse agonist)
- CI:
-
Confidence interval
- CP55,940:
-
5–1(1,1-Dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol
- CRF:
-
Corticotropin-releasing factor
- CRF1:
-
Corticotropin-releasing factor Type I receptor
- CUD:
-
Cannabinoid use disorder(s)
- ∆9-THC:
-
Delta-9-tetrahydrocannabinol
- ED50 :
-
Mean effective dose
- GPCR:
-
G protein-coupled receptor
- GRK:
-
G protein-coupled receptor kinase
- GTPγS:
-
Guanosine 5’-O-[gamma-thio]triphosphate
- HU210:
-
(6AR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol
- IP:
-
Intraperitoneal
- JNK:
-
C-Jun N-terminal kinases
- KI:
-
Knock-in
- %MPE:
-
Percentage of maximal possible effect
- OVX:
-
Ovariectomized
- SEM:
-
Standard error of the mean
- SC:
-
Subcutaneous
- Veh:
-
Vehicle
- WIN55,212–2:
-
R-( +)-[2,3-Dihydro-5-methyl-3-[(morpholinyl-methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-mapthalenyl)methanone mesylate
- WT:
-
Wild-type
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Acknowledgements
This research was supported by the National Institute on Drug Abuse grants DA037355 (DJM) and DA044999 (DJM), the Penn State University College of Medicine Department of Anesthesiology & Perioperative Medicine, Marshall University’s Department of Biomedical Sciences, and a grant from the Pennsylvania Department of Health using CURE Tobacco Settlement Funds (DJM).
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Henderson-Redmond, A.N., Sepulveda, D.E., Ferguson, E.L. et al. Sex-specific mechanisms of tolerance for the cannabinoid agonists CP55,940 and delta-9-tetrahydrocannabinol (Δ9-THC). Psychopharmacology 239, 1289–1309 (2022). https://doi.org/10.1007/s00213-021-05886-9
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DOI: https://doi.org/10.1007/s00213-021-05886-9