Role of primary sensory neurone cannabinoid type-1 receptors in pain and the analgesic effects of the peripherally acting agonist CB-13 in mice

Background: Cannabinoid type-1 receptors (CB₁Rs) are expressed in primary sensory neurones, but their role in pain modulation remains unclear. Methods: We produced Pirt-CB₁R conditional knockout (cKO) mice to delete CB₁Rs in primary sensory neurones selectively, and used behavioural, pharmacological, and electrophysiological approaches to examine the influence of peripheral CB₁R signalling on nociceptive and inflammatory pain. Results: Conditional knockout of Pirt-CB₁R did not alter mechanical or heat nociceptive thresholds, complete Freund adjuvant-induced inflammation, or heat hyperalgesia in vivo. The intrinsic membrane properties of small-diameter dorsal root ganglion neurones were also comparable between cKO and wild-type mice. Systemic administration of CB-13, a peripherally restricted CB₁/CB₂R dual agonist (5 mg kg⁻¹), inhibited nociceptive pain and complete Freund adjuvant-induced inflammatory pain. These effects of CB-13 were diminished in Pirt-CB₁R cKO mice. In small-diameter neurones from wild-type mice, CB-13 concentration-dependently inhibited high-voltage activated calcium current (HVA-I_Ca) and induced a rightward shift of the channel open probability curve. The effects of CB-13 were significantly attenuated by AM6545 (a CB₁R antagonist) and Pirt-CB₁R cKO. Conclusion: CB₁R signalling in primary sensory neurones did not inhibit nociceptive or inflammatory pain, or the intrinsic excitability of nociceptive neurones. However, peripheral CB₁Rs are important for the analgesic effects of systemically administered CB-13. In addition, HVA-I_Ca inhibition appears to be a key ionic mechanism for CB-13-induced pain inhibition. Thus, peripherally restricted CB₁R agonists could have utility for pain treatment.