The Spinal Antinociceptive Effects of a Novel Competitive AMPA Receptor Antagonist, YM872, on Thermal or Formalin-Induced Pain in Rats

Abstract

A novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, YM872, may have an analgesic effect on both acute and chronic pain when administered intrathecally.

Spinal neurotoxicity and tolerance after repeated intrathecal administration of YM 872, an AMPA receptor antagonist, in rats

“…Solutions of 1 µg (2.86 nmol; ED 50 for the tail-flick test, as used in our previous study [6]) per 10 µl were made, using normal saline, before each injection. Normal saline 10 µl was used as the control.…”

“…The analgesic effect was tested by the tail-flick test. We measured tail-flick latency and checked the side effects 15 min after the drug injection, because both the analgesic and side effects were greatest at that time in our previous study [6]. On the 31st day, the rats were killed with an overdose of halothane.…”

“…NMDA receptor antagonists except for ketamine lack clinical value because of their side effects, such as a psychotomimetic action [2], learning impairment [3], and neurotoxicity [4]. On the other hand, it has been suggested that AMPA receptors have a role in both acute and persistent inflammatory pain in the spinal cord [5,6]. In our previous studies, a new AMPA receptor antagonist, YM 872 {[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl] acetic acid; Yamanouchi Pharmaceutical, Tsukuba, Japan} showed analgesic effects on both acute thermal pain (50% effective dose; ED 50 ϭ 1 µg) and formalin-induced inflammatory pain (ED 50 ϭ 0.24 µg in phase 1 and 0.21 µg in phase 2) in rats [6].…”

“…On the other hand, it has been suggested that AMPA receptors have a role in both acute and persistent inflammatory pain in the spinal cord [5,6]. In our previous studies, a new AMPA receptor antagonist, YM 872 {[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl] acetic acid; Yamanouchi Pharmaceutical, Tsukuba, Japan} showed analgesic effects on both acute thermal pain (50% effective dose; ED 50 ϭ 1 µg) and formalin-induced inflammatory pain (ED 50 ϭ 0.24 µg in phase 1 and 0.21 µg in phase 2) in rats [6]. However, YM 872 induced transient motor disturbance and flaccidity at doses of more than 10 µg [6].…”

“…In our previous studies, a new AMPA receptor antagonist, YM 872 {[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl] acetic acid; Yamanouchi Pharmaceutical, Tsukuba, Japan} showed analgesic effects on both acute thermal pain (50% effective dose; ED 50 ϭ 1 µg) and formalin-induced inflammatory pain (ED 50 ϭ 0.24 µg in phase 1 and 0.21 µg in phase 2) in rats [6]. However, YM 872 induced transient motor disturbance and flaccidity at doses of more than 10 µg [6]. Although YM 872 had no neurotoxicity in cat brain [7], its toxicity in other organs should be elucidated before its clinical application.…”