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 i n 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-induc ed 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 h indpaw. 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 allod ynia when given systemically. SIB-1757 produced full reversal of thermal hy peralgesia 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 rec eptor may be associated with afferent C-fibers. The less impressive effect seen on tactile allodynia, likely to be mediated by large fiber input, sugg ests that the observed modulation may be related to blockade of mGluR5-medi ated spinal sensitization. These results do not support the involvement of these receptors in modulation of acute nociception but suggest the possibil ity of a role for Group I mGluRs in the mediation of aspects of neuropathic pain which may be associated with C-fiber inputs. (C) 2000 Elsevier Scienc e Ireland Ltd. All rights reserved.