SYM‐2081 A Kainate Receptor Antagonist Reduces Allodynia And Hyperalgesia In A Freeze Injury Model Of Neuropathic Pain

Abstract

Cold‐freeze injury at −4 degrees C to the rat sciatic nerve produces mechanical allodynia and thermal hyperalgesia [M.A. Kleive, P.S. Jungbluth, J.A. Uhlenkamp, K.C. Kajander, Cold injury to rat sciatic nerve induces thermal hyperalgesia or analgesia, 8th World Congress on Pain, Vancouver, BC, Canada, August 1996 (Abstract).]. The NMDA receptor, an excitatory amino acid (EAA) receptor, appears to be involved in the development of allodynia and hyperalgesia following nerve injury. The role, if any, of the kainate receptor, another EAA receptor, remains unknown. In the current study, we evaluated whether (2S,4R)‐4‐methylglutamic acid (SYM‐2081), a recently developed kainate receptor antagonist, attenuates increased responsiveness following cold injury to the sciatic nerve. During baseline testing, Sprague‐Dawley rats were evaluated for frequency of withdrawal from van Frey filaments and latency of withdrawal from a radiant thermal source. Animals were then anesthetized, the left sciatic nerve was exposed, and the nerve was cooled to −4 degrees C for 15 min (n = 24). For control rats (n = 24), all procedures were identical except that the nerve was maintained at 37 degrees C. Testing resumed on the third day following surgery. On the fifth post‐operative day, SYM‐2081 (150 or 100 mg/kg), fentanyl citrate (0.04 mg/kg) or vehicle was injected intraperitoneally. Injury to the rat sciatic nerve induced a significant increase in withdrawal frequency and a significant decrease in withdrawal latency (ANOVA, p < 0.05). SYM‐2081 and fentanyl significantly reduced these responses (p < 0.05). These results suggest that kainate and opioid receptors are involved in the mechanical allodynia and thermal hyperalgesia that develop following cold injury to the sciatic nerve.

Effect of 2-(Phosphono-methyl)-pentanedioic Acid on Allodynia and Afferent Ectopic Discharges in a Rat Model of Neuropathic Pain

“…Na ϩ and Ca 2ϩ channels are known to contribute importantly to the generation of ectopic discharge activity following nerve injury (Matzner and Devor, 1994;Xiao and Bennett, 1995). Glutamate has been implicated in the generation and maintenance of neuropathic pain because systemic administration of glutamate receptor antagonists relieves neuropathic pain (Hao and Xu, 1996;Sutton et al, 1999;Ta et al, 2000). One important source of glutamate accumulation is likely through the GCP II pathway.…”

Kainate Receptors Mediate Regulated Exocytosis of Secretory Phospholipase A2 in SH-SY5Y Neuroblastoma Cells

“…Our findings of high-level expression of sPLA 2 -IIA in the dorsal horn and spinal trigeminal nucleus [6] and the present link with KA receptors are consistent with a role of these receptors and sPLA 2 in nociceptive transmission. Intraperitoneal injection of the KA receptor antagonist SYM 2081 reduced mechanical allodynia and thermal hyperalgesia after chronic-constriction nerve injury [88] or freeze injury [89] . The GluR5 antagonist LY 382884 produced antinociceptive responses to formalin in rats [90] .…”

Antiallodynic and Antihyperalgesic Effects of Selective Competitive GLUK5 (GluR5) Ionotropic Glutamate Receptor Antagonists in the Capsaicin and Carrageenan Models in Rats

“…Furthermore, Procter et al (1998) demonstrated that LY382884 and LY294486 (the racemate of LY377770), but not the AMPA receptor-selective antagonist GYKI 53655, reduced nociceptive responses recorded electrophysiologically from hemisected spinal cords from neonatal rats in vitro as well as from dorsal horn neurons in adult rats in vivo and in the hot-plate test in conscious mice. Moreover, Ta et al (2000) found that SYM-2081 reduced mechanical allodynia and thermal hyperalgesia in a freeze nerve injury model of neuropathic pain. In addition, LY382884 attenuated the responses of spinothalamic tract neurons to mechanical and thermal stimuli in normal and neuropathic monkeys (Palecek et al, 2004).…”