Assessing CB1 and CB2 receptor agonist antinociception while exploring sex differences and 5-HT1A-dependent mechanisms
- 1Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- 2Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- 3Brain Drug Discovery Center, Texas Tech University Health Sciences Center, Amarillo, TX, United States
Abstract
IntroductionInflammatory pain is a key component of both acute and chronic pain conditions that, when pathological, significantly decrease patient quality of life. There has been a recent interest in the use of cannabinoid-based compounds for analgesia and recent research has discovered functional connections between the CB2 and 5-HT1A receptors.MethodsTherefore, we investigated the efficacy of CB1-selective agonism (ACEA) and CB2-selective agonism (AM1241), and their potential reliance on the 5-HT1A receptor, in the formalin inflammatory pain model using female and male adult C57BL/6J mice. Potential dose- and sex-differences were assessed for ACEA (at 0.1-2.5 mg/kg) and AM1241 (at 1-10 mg/kg) in the formalin test. Subsequent experiments were conducted using either ACEA (0.5 mg/kg) or AM1241 (10 mg/kg), alone or with inhibition of 5-HT1A via WAY-100635, in both the formalin model of inflammatory pain and the non-nociceptive components of the cannabinoid tetrad test (open field, rotarod, rectal temperature).ResultsACEA provided significant pain relief at 0.5 mg/kg in female mice and at 0.5 and 0.75 mg/kg in male mice, with significant sex differences observed. ACEA (0.5 mg/kg) antinociception was unaltered by 5-HT1A inhibition while AM1241 (10 mg/kg) antinociception was completely prevented in the acute phase by 5-HT1A inhibition. Neither ACEA nor AM1241 significantly altered performance in the open field, rotarod, or rectal temperature assessments.DiscussionThese results demonstrate the antinociceptive benefit of CB1 and CB2 agonism in a murine model of inflammatory pain while demonstrating further evidence of a functional link between the CB2 and 5-HT1A receptors. Further studies are needed to investigate the mechanism behind this connection and its potential clinical significance.
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BibTeX
@article{barnes2026assessing,
title = {{Assessing CB1 and CB2 receptor agonist antinociception while exploring sex differences and 5-HT1A-dependent mechanisms}},
author = {Robert C. Barnes and Hannah Quick and Dakota Robison and Aric F. Logsdon and Aric F. Logsdon and Aric F. Logsdon and Josée Guindon and Josée Guindon},
journal = {Frontiers in Pain Research},
year = {2026},
month = oct,
doi = {10.3389/fpain.2026.2005000},
url = {https://doi.org/10.3389/fpain.2026.2005000},
note = {CC BY},
}
RIS
TY - JOUR
TI - Assessing CB1 and CB2 receptor agonist antinociception while exploring sex differences and 5-HT1A-dependent mechanisms
AU - Robert C. Barnes
AU - Hannah Quick
AU - Dakota Robison
AU - Aric F. Logsdon
AU - Aric F. Logsdon
AU - Aric F. Logsdon
AU - Josée Guindon
AU - Josée Guindon
PY - 2026
DA - 2026/10/26
JO - Frontiers in Pain Research
DO - 10.3389/fpain.2026.2005000
UR - https://doi.org/10.3389/fpain.2026.2005000
AB - IntroductionInflammatory pain is a key component of both acute and chronic pain conditions that, when pathological, significantly decrease patient quality of life. There has been a recent interest in the use of cannabinoid-based compounds for analgesia and recent research has discovered functional connections between the CB2 and 5-HT1A receptors.MethodsTherefore, we investigated the efficacy of CB1-selective agonism (ACEA) and CB2-selective agonism (AM1241), and their potential reliance on the 5-HT1A receptor, in the formalin inflammatory pain model using female and male adult C57BL/6J mice. Potential dose- and sex-differences were assessed for ACEA (at 0.1-2.5 mg/kg) and AM1241 (at 1-10 mg/kg) in the formalin test. Subsequent experiments were conducted using either ACEA (0.5 mg/kg) or AM1241 (10 mg/kg), alone or with inhibition of 5-HT1A via WAY-100635, in both the formalin model of inflammatory pain and the non-nociceptive components of the cannabinoid tetrad test (open field, rotarod, rectal temperature).ResultsACEA provided significant pain relief at 0.5 mg/kg in female mice and at 0.5 and 0.75 mg/kg in male mice, with significant sex differences observed. ACEA (0.5 mg/kg) antinociception was unaltered by 5-HT1A inhibition while AM1241 (10 mg/kg) antinociception was completely prevented in the acute phase by 5-HT1A inhibition. Neither ACEA nor AM1241 significantly altered performance in the open field, rotarod, or rectal temperature assessments.DiscussionThese results demonstrate the antinociceptive benefit of CB1 and CB2 agonism in a murine model of inflammatory pain while demonstrating further evidence of a functional link between the CB2 and 5-HT1A receptors. Further studies are needed to investigate the mechanism behind this connection and its potential clinical significance.
SN - 2673-561X
ER -