Peripheral and spinal antihyperalgesic activity of SIB-1757, a metabotropic glutamate receptor (mGLUR(5)) antagonist, in experimental neuropathic pain in rats.
Recent studies suggest a role of Group 1 metabotropic glutamate receptors in mediating the development of spinal hypersensitivity in some pain states. Here, the possible role of mGluR(5) receptors in experimental neuropathic pain elicited by ligation of spinal nerves (L(5)/L(6) spinal nerve ligation, SNL) was explored with SIB-1757, a selective mGluR(5) antagonist. SNL-induced tactile allodynia was detected by decreased paw withdrawal thresholds to probing with von Frey filaments and thermal hyperalgesia by decreased paw withdrawal latencies to radiant heat applied to the plantar aspect of the hindpaw. SIB-1757 was given by either intrathecal (i.th.), subcutaneous (s.c.) or intraplantar (i.pl.) injection. In SNL rats, i.th. SIB-1757 produced a partial reversal of tactile allodynia with a shallow dose-response curve ranging over three-orders of magnitude; SIB-1757 was inactive against allodynia when given systemically. SIB-1757 produced full reversal of thermal hyperalgesia in SNL rats following administration either spinally or locally to the injured paw; administration to the contralateral paw had no effect. SIB-1757 did not produce antinociception in either the SNL or sham-operated rats by any route. These data suggest a significant modulation of thermal hyperalgesia by mGluR(5) antagonists, consistent with reports that this receptor may be associated with afferent C-fibers. The less impressive effect seen on tactile allodynia, likely to be mediated by large fiber input, suggests that the observed modulation may be related to blockade of mGluR(5)-mediated spinal sensitization. These results do not support the involvement of these receptors in modulation of acute nociception but suggest the possibility of a role for Group I mGluRs in the mediation of aspects of neuropathic pain which may be associated with C-fiber inputs.
Dogrul
A
A
Department of Pharmacology, Faculty of Medicine, Gulhane Medical Military Academy, Ankara, Turkey.
Ossipov
M H
MH
Lai
J
J
Malan
T P
TP
Porreca
F
F
D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy*; D008026:Ligation; D008297:Male; D009412:Nerve Fibers / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects; D010621:Phenazopyridine / Q000494:pharmacology*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013127:Spinal Nerves / Q000601:surgery
D018691:Excitatory Amino Acid Antagonists; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C120147:SIB 1757; D010621:Phenazopyridine