title: The inhibition of nitric oxide-activated poly(ADP-ribose) synthetase attenuates transsynaptic alteration of spinal cord dorsal horn neurons and neuropathic pain in the rat.
abstract: Transsynaptic alteration of spinal cord dorsal horn neurons characterized 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 glutamate-induced neurotoxicity. In the present study, we examined whether the inhibition of the nitric oxide (NO)-activated poly(ADP-ribose) synthetase (PARS), a nuclear enzyme critical to glutamate-induced neurotoxicity, would both reduce the incidence of dark neurons and attenuate behavioral 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 rats. The number of dark neurons in the dorsal horn was dose-dependently reduced in CCI rats receiving once daily intrathecal (i.t.) treatment with the PARS inhibitor benzamide (200 or 400 nmol, but not 100 nmol benzamide or saline) for 7 days. Consistent with the histological improvement, thermal hyperalgesia, mechanical hyperalgesia, and low threshold mechano-allodynia also were reliably reduced in CCI rats treated with either 200 or 400 nmol benzamide. Neither dark neurons nor neuropathic 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 selective effect of benzamide. Intrathecal treatment with an NO synthase inhibitor NG-nitro-L-arginine methyl ester (40 nmol, but not its inactive D-isomer) utilizing the same benzamide treatment regimen resulted in similar reductions of both dark neurons and neuropathic pain behaviors in CCI rats. These results provide, for the first time, in vivo evidence indicating that benzamide is neuroprotective and that the PARS-mediated transsynaptic alteration of spinal cord dorsal horn neurons contributes to behavioral manifestations of neuropathic pain in CCI rats. These observations may have general implications beyond treatment of neuropathic pain in that PARS-mediated neuronal alterations may play a significant role in glutamate-mediated neurotoxicity under many other circumstances.
authors.affiliation: Department of Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0516, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mao
authors.forename: D D
authors.initials: DD
authors.lastname: Price
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: D J
authors.initials: DJ
authors.lastname: Mayer
mesh_terms: D036002:ADP Ribose Transferases; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D009422:Nervous System Diseases / Q000503:physiopathology*; D009474:Neurons / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology*; D013569:Synapses / Q000502:physiology*
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009569:Nitric Oxide; C037689:benzamide; D036002:ADP Ribose Transferases