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The CBD-induced decrease in mechanical and cold allodynia was unaffected by GW9662, which is consistent with its high affinity for PPARgamma, but unaffected by AM251 and AM630, which is consistent with their limited binding affinity for PPARs compared to GW9662 . Thus, the role of cannabinoid CB1 and CB2 receptors was variable if not opposite to THC-induced responses. These observations suggest that the biological actions of THC, CBD and other phytocannabinoids are highly differentiated. This is consistent with the observation that THC/CBD may have opposing effects on opioid receptors in the spinal cord [42,43].
The actions of cannabinoids varied greatly between chronic pain models. For example, the THC-induced decreases in mechanical allodynia were abolished by AM281 or AM630 in models of neuropathic pain induced by CCI or chronic paclitaxel treatment. In contrast, this post synaptic cannabinoid receptor activity of spinal dorsal horn neurons was required for the expected anti-nociceptive effects of centrally-administered cannabinoids in this model of thermonociceptive chronic pain . This likely reflected the high levels of CB1 receptor expression in peripheral nerve endings compared to spinal nociceptive neurons that are post synaptic to CB1 receptor containing terminals. This suggests that the effects of endogenously-released cannabinoids will also have site-specific variability. This may explain the lack of cannabinoid CB1 receptor-mediated analgesia in models using other methods of nerve injury, and the lack of cannabinoid CB1 receptors in the spinal cord of peptidergic nerve injured animals [45,46].
The THC-induced reduction in cold allodynia was unaffected by the cannabinoid CB1 receptor antagonist AM251 and partly reduced by the cannabinoid CB2 receptor antagonist AM630. These observations were consistent with prior intrathecal studies using cannabinoid CB1 receptor agonist [23,24]. It is possible that THC may also reduce cold allodynia via activation of CB2 receptors in the dorsal horn [27,28], or by supressing coricause output from other cannabinoid rich cell types in the dorsal horn [47,48].