Spinal dorsal horn neurons involved in the alleviating effects of cannabinoid receptor agonists on neuropathic allodynia-like behaviors in rats

Mechanical allodynia, the pain caused by innocuous tactile stimuli, is a hallmark symptom of neuropathic pain that is often resistant to currently available treatments. Cannabinoids are widely used for pain management; however, their therapeutic mechanisms for neuropathic mechanical allodynia remain unclear. Using transgenic rats that enable to optogenetically stimulate touch-sensing A(3 fibers in the skin, we found that the intrathecal administration of the synthetic cannabinoid, WIN 55,212-2, alleviated the A(3 fiber-derived neuropathic allodynia. Furthermore, we injected adeno-associated virus vectors incorporating the rat cannabinoid receptor 1 (CB1 receptor) (encoded by Cnr1) promoter and tdTomato or short hairpin RNA targeting the CB1 receptor into the spinal dorsal horn (SDH) and demonstrated that the conditional knockdown of CB1 receptors in Cnr1+ SDH neurons attenuates the anti-allodynic effects of intrathecally administered WIN 55,212-2. Electrophysiological analysis revealed that Cnr1+ SDH neurons received excitatory synaptic inputs from the primary afferent A(3 fibers. Collectively, our results suggest that the CB1 receptors in Cnr1+ SDH neurons are molecular and cellular targets of intrathecal WIN 55,212-2 to alleviate neuropathic allodynia.