Angela N Henderson-Redmond1,2,3, Diana E Sepulveda4,5, Erin L Ferguson5, Aaron M Kline5, Mary K Piscura6,5, Daniel J Morgan6,4,5,7. 1. Department of Biomedical Sciences, Marshall University, Huntington, WV, 25755, USA. redmonda@marshall.edu. 2. Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, 17033, USA. redmonda@marshall.edu. 3. Anesthesiology and Perioperative Medicine, Penn State University College of Medicine, Hershey, PA, 17033, USA. redmonda@marshall.edu. 4. Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, 17033, USA. 5. Anesthesiology and Perioperative Medicine, Penn State University College of Medicine, Hershey, PA, 17033, USA. 6. Department of Biomedical Sciences, Marshall University, Huntington, WV, 25755, USA. 7. Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA, 17033, USA.
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.
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.
Authors: Cynthia I Campbell; Constance Weisner; Linda Leresche; G Thomas Ray; Kathleen Saunders; Mark D Sullivan; Caleb J Banta-Green; Joseph O Merrill; Michael J Silverberg; Denise Boudreau; Derek D Satre; Michael Von Korff Journal: Am J Public Health Date: 2010-08-19 Impact factor: 9.308
Authors: Denise Boudreau; Michael Von Korff; Carolyn M Rutter; Kathleen Saunders; G Thomas Ray; Mark D Sullivan; Cynthia I Campbell; Joseph O Merrill; Michael J Silverberg; Caleb Banta-Green; Constance Weisner Journal: Pharmacoepidemiol Drug Saf Date: 2009-12 Impact factor: 2.890
Authors: Hye Ji J Kim; Ayat Zagzoog; Anna Maria Smolyakova; Udoka C Ezeaka; Michael J Benko; Teagan Holt; Robert B Laprairie Journal: Front Neurosci Date: 2021-12-21 Impact factor: 4.677