Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain.
Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-N(G)-nitro-arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2h) and maintenance (24h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.
Chu
Ya-Chun
YC
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 355 Ross, 720 Rutland Avenue, Baltimore, MD 21205, USA Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC.
Guan
Yun
Y
Skinner
John
J
Raja
Srinivasa N
SN
Johns
Roger A
RA
Tao
Yuan-Xiang
YX
D000818:Animals; D001522:Behavior, Animal; D002908:Chronic Disease; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009437:Neuralgia / Q000139:chemically induced / Q000503:physiopathology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D017288:Pain Threshold; D020671:Posterior Horn Cells / Q000187:drug effects / Q000503:physiopathology*
D005620:Freund's Adjuvant; D052248:Nitric Oxide Synthase Type I; D019331:NG-Nitroarginine Methyl Ester