Antinociceptive property of intrathecal and intraperitoneal administration of a novel water-soluble isoindolin-1-one derivative, JM 1232 (-) in rats.
Antinociceptive effects of a new water-soluble sedative agent, an isoindolin-1-one derivative, (-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta[f]isoindol-1-(2H)-one (JM 1232 (-)) were studied in two different nociceptive models of rats. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and for their paw flinches by formalin injection after intrathecal administration of various doses of JM 1232 (-). The effects of intraperitoneal administration were also investigated. In addition, behavioral side effects were examined. When antinociceptive effects were observed, the effects of pretreatment with flumazenil or naloxone for the maximum effective dose were evaluated. Eight rats were used in each dose of each group. Intrathecal JM 1232 (-) increased the tail flick latency and decreased the number of flinches in both phases 1 and 2 of the formalin test. These changes were antagonized by intrathecal flumazenil but not by naloxone. Intraperitoneal JM 1232 (-) had no effects on the tail flick latency, but decreased the number of flinches in both phases 1 and 2 of the formalin test. The latter was antagonized by intraperitoneal flumazenil and naloxone with bigger effects of flumazenil. Intraperitoneal JM 1232 (-) 3000 microg induced reversible motor disturbance. In conclusion, intrathecal JM 1232 (-) exerts antinociceptive effects on acute thermal and inflammatory stimuli through benzodiazepine-GABA(A) receptors in the spinal cord. Intraperitoneal JM 1232 (-) was antinociceptive only against inflammatory stimulus and this is mediated mainly by benzodiazepine-GABA(A) receptors, but partially by micro-opioid receptors in the brain.
Nishiyama
Tomoki
T
Department of Anesthesiology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. nishit-tky@umin.ac.jp
Chiba
Shunsuke
S
Yamada
Yoshitsugu
Y
D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D054833:Isoindoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D010147:Pain Measurement; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water
C534223:3-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta(f)isoindol-1(2H)-one; D000700:Analgesics; D054833:Isoindoles; D010879:Piperazines; D014867:Water