Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain.
Nitric oxide generated by the nitric oxide synthase (NOS) isoforms contributes to pain processing. The selective inhibition of iNOS might represent a novel, therapeutic target for the development of antinociceptive compounds. However, few isoform-selective inhibitors of NOS have been developed. The present experiments examined the anti-inflammatory and antinociceptive activity of a selective inducible nitric oxide (iNOS) inhibitor, AR-C102222, on arachidonic acid-induced ear inflammation, Freund's complete adjuvant (FCA)-induced hyperalgesia, acetic acid-induced writhing, and tactile allodynia produced by L5 spinal nerve ligation (L5 SNL) or hindpaw incision (INC). AR-C102222 at a dose of 100mg/kg p.o., significantly reduced inflammation produced by the application of arachidonic acid to the ear, attenuated FCA-induced mechanical hyperalgesia, and attenuated acetic acid-induced writhing. In the L5 SNL and INC surgical procedures, tactile allodynia produced by both procedures was significantly reduced by 30mg/kg i.p. of AR-C102222. These data demonstrate that the selective inhibition of iNOS produces antinociception in different models of pain and suggest that the iNOS-NO system plays a role in pain processing.
LaBuda
Christopher J
CJ
Department of Pharmacology, Adolor Corporation, Exton, PA 19341, USA. clabuda@adolor.com
Koblish
Michael
M
Tuthill
Paul
P
Dolle
Roland E
RE
Little
Patrick J
PJ
D000818:Animals; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D020422:Mononeuropathies / Q000150:complications / Q000188:drug therapy*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
C489944:AR C102222AA; D011799:Quinazolines; D019001:Nitric Oxide Synthase