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 delta-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 delta-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 micro g, dose-dependently increased the withdrawal threshold in response to the noxious pressure in normal and diabetic rats. However, the ED(50) 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.
Chen
Shao-Rui
SR
Department of Anesthesiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033-0850, USA.
Pan
Hui-Lin
HL
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D010146:Pain / Q000209:etiology*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D020881:Enkephalin, D-Penicillamine (2,5)-; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat