Rapid development of nitric oxide-induced hyperalgesia depends on an alternate to the cGMP-mediated pathway in the rat neuropathic pain model.
Intrathecal injection of a nitric oxide releasing compound, NOC-18, was used to define the role of nitric oxide (NO) in the spinal mechanism of neuropathic pain caused by unilateral chronic constriction injury to rat sciatic nerves. Paw withdrawal latency was used to evaluate nociception induced by thermal stimuli before surgery and afterwards at 1, 3, and 6 h, and on days 1, 2, 3, 4, 5, 8, and 12 after the nerve ligature. In the sham-surgery control groups, intrathecal injection of 10 or 100 microg of NOC-18 did not produce any change in withdrawal latencies. In rats with unilateral nerve ligation, however, administration of 1 or 10 microg, but not 0.1 microg, of NOC-18 significantly shortened the time in which thermal hyperalgesia developed after nerve injury. Injection of 1 microg of NOC-18 decreased the onset time of thermal hyperalgesia from 2 days to 3 h and with 10 microg hyperalgesia developed within 1 h after the nerve injury. The effects of intrathecal injection of MK-801, a N-methyl-D-aspartate (NMDA) receptor antagonist, N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, methylene blue (MB), a soluble guanylate cyclase inhibitor, and hemoglobin (Hb), a NO scavenger, on the development of thermal hyperalgesia after the sciatic nerve ligature were examined in the presence and absence of 1 and 10 microg of NOC-18. Acceleration of the development of thermal hyperalgesia induced by 1 and 10 microg NOC-18 was completely inhibited by Hb, but was not affected by either MK-801, L-NAME or MB. These findings indicate that NO plays an important role in the rapid development of thermal hyperalgesia after the nerve injury, but that facilitation of nociceptive processing in the spinal cord may entail an alternate to the NO-cyclic guanosine 3',5'-monophosphate (cGMP) pathway.
Inoue
T
T
Department of Anesthesiology, Osaka University Medical School, Yamadaoka 2-2, Suita City, Osaka 565, Japan. inoue@anes.med.osaka-u.ac.jp
Mashimo
T
T
Shibata
M
M
Shibuta
S
S
Yoshiya
I
I
D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006454:Hemoglobins / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D008026:Ligation; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries; D013116:Spinal Cord / Q000378:metabolism
D000931:Antidotes; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006454:Hemoglobins; C093285:NOC 18; D009603:Nitroso Compounds; D009569:Nitric Oxide; D016291:Dizocilpine Maleate; D006152:Cyclic GMP; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester