THE INHIBITION OF NITRIC OXIDE-ACTIVATED POLY(ADP-RIBOSE) SYNTHETASE ATTENUATES TRANSSYNAPTIC ALTERATION OF SPINAL-CORD DORSAL HORN NEURONSAND NEUROPATHIC PAIN IN THE RAT

Transsynaptic alteration of spinal cord dorsal horn neurons characteri zed by hyperchromatosis of cytoplasm and nucleoplasm (so-called 'dark' neurons) occurs in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the common sciatic nerve. The incidence of dark neurons in CCI rats has been proposed to be mediated by glutam ate-induced neurotoxicity. In the present study, we examined whether t he inhibition of the nitric oxide (NO)-activated poly(ADP-ribose) synt hetase (PARS), a nuclear enzyme critical to glutamate-induced neurotox icity, would both reduce the incidence of dark neurons and attenuate b ehavioral manifestations of neuropathic pain in CCI rats. Dark neurons were observed bilaterally (with ipsilateral predominance) within the spinal cord dorsal horn, particularly in laminae I-II, of rats 8 days after unilateral sciatic nerve ligation as compared to sham operated r ats. The number of dark neurons in the dorsal horn was dose-dependentl y reduced in CCI rats receiving once daily intrathecal (i.t.) treatmen t with the PARS inhibitor benzamide (200 or 400 nmol, but not 100 nmol benzamide or saline) for 7 days. Consistent with the histological imp rovement, thermal hyperalgesia, mechanical hyperalgesia, and low thres hold mechano-allodynia also were reliably reduced in CCI rats treated with either 200 or 400 nmol benzamide. Neither dark neurons nor neurop athic pain behaviors were reliably affected by i.t. administration of either 800 nmol novobiocin (a mono(ADP-ribose) synthetase) or 800 nmol benzoic acid (the backbone structure of benzamide), indicating a sele ctive effect of benzamide. Intrathecal treatment with an NO synthase i nhibitor N-G-nitro-L-arginine methyl ester (40 nmol, but not its inact ive D-isomer) utilizing the same benzamide treatment regimen resulted in similar reductions of both dark neurons and neuropathic pain behavi ors in CCI rats. These results provide, for the first time, in vivo ev idence indicating that benzamide is neuroprotective and that the PARS- mediated transsynaptic alteration of spinal cord dorsal horn neurons c ontributes to behavioral manifestations of neuropathic pain in CCI rat s. These observations may have general implications beyond treatment o f neuropathic pain in that PARS-mediated neuronal alterations may play a significant role in glutamate-mediated neurotoxicity under many oth er circumstances. (C) 1997 International Association for the Study of Pain. Published by Elsevier Science B.V.