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 (CBRs) are expressed in primary sensory neurones, but their role in pain modulation remains unclear.

METHODS

We produced Pirt-CBR conditional knockout (cKO) mice to delete CBRs in primary sensory neurones selectively, and used behavioural, pharmacological, and electrophysiological approaches to examine the influence of peripheral CBR signalling on nociceptive and inflammatory pain.

RESULTS

Conditional knockout of Pirt-CBR 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 CB/CBR dual agonist (5 mg kg), inhibited nociceptive pain and complete Freund adjuvant-induced inflammatory pain. These effects of CB-13 were diminished in Pirt-CBR cKO mice. In small-diameter neurones from wild-type mice, CB-13 concentration-dependently inhibited high-voltage activated calcium current (HVA-I) and induced a rightward shift of the channel open probability curve. The effects of CB-13 were significantly attenuated by AM6545 (a CBR antagonist) and Pirt-CBR cKO.

CONCLUSION

CBR signalling in primary sensory neurones did not inhibit nociceptive or inflammatory pain, or the intrinsic excitability of nociceptive neurones. However, peripheral CBRs are important for the analgesic effects of systemically administered CB-13. In addition, HVA-I inhibition appears to be a key ionic mechanism for CB-13-induced pain inhibition. Thus, peripherally restricted CBR agonists could have utility for pain treatment.