Attenuation of cannabinoid-induced inhibition of medullary dorsal horn neurons by a kappa-opioid receptor antagonist

The kappa-opioid receptor (KOR) antagonist norbinaltorphimine (nor-BNI) attenuates behavioral antinociception produced by spinal administration of the cannabinoid receptor agonist delta-9-tetrahydorcannabinol (THC). The present study examined the ability of nor-BNI to prevent cannabinoid-induced inhibition of medullary dorsal horn (MDH) nociceptive neurons and antinociception produced by the cannabinoid agonist WIN 55,212-2 (WIN-2). Extracellular, single-unit recordings of lamina I and lamina V MDH neurons were performed in urethane anesthetized rats. Heat-evoked activity was measured before and after local brainstem application of nor-BNI or vehicle followed by WIN-2. In both lamina I and lamina V neurons, prior application of nor-BNI prevented the inhibition of heat-evoked activity by WIN-2. In separate experiments, the contribution of KOR to cannabinoid-induced increases in heat-evoked head withdrawal latencies was assessed in lightly urethane-anesthetized rats. Antinociception produced by intrathecal administration of WIN-2 and THC was attenuated by prior administration of nor-BNI. In contrast, antinociception produced by the cannabinoid CP55940 remained unaffected by prior administration of nor-BNI. These results indicate that cannabinoid inhibition of nociceptive reflexes produced by WIN-2 and THC may result from inhibition of dorsal horn neurons through a KOR-dependent mechanism.

Research Highlights
► In electrophysiology studies, a kappa-opioid receptor antagonist blocked cannabinoid-induced suppression of noxious heat-evoked activity in trigeminal neurons.
► In behavioral studies, head withdrawal latencies elicited by heat stimulation were increased by the cannabinoid receptor agonists WIN 55,212-2 and delta-9-THC and antagonized by a kappa-opioid receptor antagonist.
► These results indicate that cannabinoid inhibition of nociceptive reflexes produced by WIN-2 and THC may result from inhibition of dorsal horn neurons through a kappa-opioid receptor-dependent mechanism.