Spinal nitric oxide contributes to the analgesic effect of intrathecal [D-Pen², D-Pen⁵]-enkephalin in normal and diabetic rats

Background: Spinal nitric oxide (NO) is important for the analgesic actions of morphine and cholinergic agents. Its role in the analgesic effect of δ-opioid receptor agonists is not known. In the present study, the authors determined the role of spinal endogenous NO in the antinociceptive effect of intrathecal [D-Pen², D-Pen⁵]-enkephalin (DPDPE), a δ-opioid receptor agonist, in normal rats and a rat model of diabetic neuropathic pain. Methods: Rats were rendered diabetic with streptozotocin (50 mg/kg, intraperitoneal). Intrathecal catheters were implanted in age-matched normal and diabetic rats. Nociceptive thresholds were determined by application of a noxious pressure stimulus to the hind paw. The dose-dependent effect of intrathecal DPDPE was first determined. The role of spinal NO in the analgesic effect of intrathecal DPDPE was then examined through intrathecal treatments with NO synthase inhibitors (NMMA and TRIM) and a specific NO scavenger (carboxy-PTIO). Results: The diabetic rats developed a sustained mechanical hyperalgesia within 3 weeks after streptozotocin injection. Intrathecal DPDPE, 2-20 μg, dose-dependently increased the withdrawal threshold in response to the noxious pressure in normal and diabetic rats. However, the ED₅₀ of DPDPE in diabetic rats was about twofold higher than that in normal rats. Intrathecal pretreatment with NMMA, TRIM, or carboxy-PTIO diminished the analgesic effect of DPDPE in both normal and diabetic rats. Furthermore, the inhibitory effect of NMMA on the action of intrathecal DPDPE was reversed by intrathecal L-arginine but not D-arginine. Conclusions: Intrathecal DPDPE produces an antinociceptive effect in normal rats and a rat model of diabetic neuropathic pain. Spinal endogenous NO contributes importantly to the analgesic action of intrathecal DPDPE in both normal and diabetic neuropathic pain conditions.