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 mu g of NOC-18 did not produce any change in withdrawal latencies. In rats with unilateral nerve ligation, however, administration of 1 or 10 mu g but not 0.1 mu g, of NOC-18 significantly shortened the time in which thermal hyperalgesia developed after nerve injury. Injection of 1 mu g of NOC-18 decreased the onset time of thermal hyperalgesia from 2 days to 3 h and with 10 mu g 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 mu g of NOC-18. Acceleration of the development of thermal hyperalgesia induced by 1 and 10 mu g 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. (C) 1998 Elsevier Science B.V.