Effect of 2-(phosphono-methyl)-pentanedioic acid on allodynia and afferent ectopic discharges in a rat model of neuropathic pain.
Increased glutamate availability in the spinal cord and primary afferent nerves plays an important role in acute and chronic pain. Afferent ectopic discharges from the site of nerve injury constitute a source of abnormal sensory input to the spinal dorsal horn. The ectopic afferent activity is largely responsible for the development of hypersensitivity of dorsal horn neurons and neuropathic pain. Inhibition of glutamate carboxypeptidase II (GCP II) reduces glutamate release generated from N-acetyl-aspartyl-glutamate in nerve tissues and may have an analgesic effect on neuropathic pain. In the present study, we determined the effect of a GCP II inhibitor, 2-(phosphono-methyl)-pentanedioic acid (2-PMPA), on allodynia and ectopic afferent discharges in an animal model of neuropathic pain. Neuropathic pain was induced by partial ligation of the left sciatic nerve in rats. Tactile allodynia was assessed using von Frey filaments applied to the plantar surface of the injured hindpaw. Single-unit activity of ectopic discharges was recorded from the sciatic nerve proximal to the site of ligation. Intravenous injection of 50 to 100 mg/kg 2-PMPA significantly reduced allodynia in a dose-dependent manner. Furthermore, 2-PMPA dose-dependently attenuated the ectopic discharge activity of injured sciatic afferent nerves. At a dose of 100 mg/kg, 2-PMPA significantly inhibited the ectopic activity from 14.7 +/- 2.1 to 4.4 +/- 0.5 impulses/s without altering the conduction velocity of afferent nerves. Therefore, these data suggest that the antiallodynic effect of 2-PMPA may be mediated, at least in part, by inhibition of ectopic afferent discharges at the site of nerve injury.
Chen
Shao-Rui
SR
Department of Anesthesiology, Penn State University College of Medicine, Hershey, Pennsylvania 17033-0850, USA.
Wozniak
Krystyna M
KM
Slusher
Barbara S
BS
Pan
Hui-Lin
HL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II; D018698:Glutamic Acid / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000473:pathology
C402107:2-(phosphonomethyl)pentanedioic acid; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D018698:Glutamic Acid; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II