Faculty Collaboration Database

Conditional deletion of CB2 cannabinoid receptors from peripheral sensory neurons eliminates CB2-mediated antinociceptive efficacy in a mouse model of carrageenan-induced inflammatory pain. Neuropharmacology 2023 Oct 01;237:109601

Date

06/08/2023

Pubmed ID

37286073

Pubmed Central ID

PMC10409300

DOI

10.1016/j.neuropharm.2023.109601

Scopus ID

2-s2.0-85161662256 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

CB₂ cannabinoid receptor agonists suppress pathological pain in animal models and lack unwanted side effects commonly associated with direct activation of CB₁ receptors. However, the types of pain most responsive to CB₂ agonists are incompletely understood and cell types which underlie CB₂-mediated therapeutic efficacy remain largely unknown. We previously reported that the CB₂ receptor agonist LY2828360 reduced neuropathic nociception induced by toxic challenge with chemotherapeutic and anti-retroviral agents in mice. Whether these findings generalize to models of inflammatory pain is not known. Here we show that LY2828360 (10 mg/kg i.p.) reversed the maintenance of carrageenan-induced mechanical allodynia in female mice. Anti-allodynic efficacy was fully preserved in global CB₁ knock out (KO) mice but absent in CB₂ KO mice. The anti-allodynic efficacy of LY2828360 was absent in conditional KO (cKO) mice lacking CB₂ receptors in peripheral sensory neurons (Advillin^CRE/+; CB₂^f/f) and preserved in cKO mice lacking CB₂ receptors in microglia/macrophages expressing C-X3-C Motif Chemokine Receptor 1 (CX3CR1^CRE/+; CB₂^f/f). Intraplantar administration of LY2828360 (30 μg i.pl.) reversed carrageenan-induced mechanical allodynia in CB₂^f/f but not Advillin^CRE/+; CB₂^f/f mice of both sexes. Thus, CB₂ receptors in peripheral sensory neurons likely underlie the therapeutic effects of LY2828360 injection in the paw. Lastly, qRT-PCR analyses revealed that LY2828360 reduced carrageenan-induced increases in IL-1β and IL-10 mRNA in paw skin. Our results suggest that LY2828360 suppresses inflammatory nociception in mice through a neuronal CB₂-dependent mechanism that requires peripheral sensory neuron CB₂ receptors and suggest that the clinical applications of LY2828360 as an anti-hyperalgesic agent should be re-evaluated.

Author List

Guenther KG, Xu Z, Romero J, Hillard CJ, Mackie K, Hohmann AG

Author

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Analgesics
Animals
Carrageenan
Female
Hyperalgesia
Male
Mice
Pain
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Receptors, Cannabinoid
Sensory Receptor Cells