Antiallodynic effect of intrathecal neostigmine is mediated by spinal nitric oxide in a rat model of diabetic neuropathic pain.
BACKGROUND
Intrathecal administration of acetylcholinesterase inhibitors produces antinociception in both animals and humans, but their effect on diabetic neuropathic pain has not been studied. In the current study, we determined the antiallodynic effect of intrathecal injection of an acetylcholinesterase inhibitor, neostigmine, in a rat model of diabetic neuropathic pain. In addition, since acetylcholine can increase release of nitric oxide in the spinal cord, we studied the role of spinal endogenous nitric oxide in the action of intrathecal neostigmine in diabetic neuropathic pain.


METHODS
Rats were rendered diabetic with an intraperitoneal 50-mg/kg injection of streptozotocin. Intrathecal catheters were inserted, with tips in the lumbar intrathecal space. Mechanical allodynia was determined by application of von Frey filaments to the hind paw. We first determined the dose-dependent effect of intrathecal neostigmine on allodynia. The role of spinal nitric oxide in the action of intrathecal neostigmine was then examined through intrathecal treatments with a neuronal nitric oxide synthase inhibitor (TRIM), a nitric oxide scavenger (PTIO), L-arginine, or D-arginine.


RESULTS
The diabetic rats developed a sustained tactile allodynia within 4 weeks after streptozotocin injection. Intrathecal injection of 0.1-0.5 microg neostigmine dose-dependently increased the withdrawal threshold in response to application of von Frey filaments. Intrathecal pretreatment with 30 microg TRIM or 30 microg PTIO abolished the antiallodynic effect of intrathecal neostigmine. Furthermore, the inhibitory effect of TRIM on the action of intrathecal neostigmine was reversed by intrathecal injection of 100 microg L-arginine but not D-arginine.


CONCLUSIONS
Intrathecal neostigmine produces a profound analgesic effect in a rat model of diabetic neuropathic pain. Spinal endogenous nitric oxide contributes to the analgesic action of intrathecal neostigmine in this rat model of diabetic neuropathic pain.
Chen
S R
SR
Department of Anesthesiology, The Pennsylvania State University College of Medicine, Hershey 17033-0850, USA.
Khan
G M
GM
Pan
H L
HL
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D009388:Neostigmine / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D010146:Pain / Q000209:etiology* / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D009388:Neostigmine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat