PROSTANOIDS SYNTHESIZED BY CYCLOOXYGENASE ISOFORMS IN RAT SPINAL-CORDAND THEIR CONTRIBUTION TO THE DEVELOPMENT OF NEURONAL HYPEREXCITABILITY

1 The responses of wide dynamic range spinal dorsal horn neurones to n oxious mechanical stimulation of the ankle or knee joint were tested b efore and after spinal administration of the non-selective cyclooxygen ase (COX) inhibitors, indomethacin and meclofenamic acid. Neither of t hese drugs altered the responses of these neurones to noxious mechanic al stimulation. 2 Wind-up of a spinal nociceptive reflex evoked by ele ctrical stimulation of the sural nerve at C-fibre strength was dose-de pendently inhibited by intravenous administration of indomethacin, a n on-selective COX inhibitor, and SC58125, a selective COX-2 inhibitor. Intrathecal administration of indomethacin also reduced the wind-up of this nociceptive reflex. 3 Western blot analysis of proteins extracte d from normal rat spinal cord revealed the presence of both cyclo-oxyg enase (COX)-1 and COX-2 proteins. 4 Immunocytochemistry of sections of normal rat spinal cord with specific COX-1 antiserum revealed little specific COX-1-like immunoreactivity in the grey matter. With the same antiserum, intense COX-1-like immunoreactivity was observed in the cy toplasm, nuclear membrane and axonal processes of small to medium size d (<1000 mu m(2)) dorsal root ganglion (DRG) cell bodies. 5 Immunocyto chemistry of sections of normal rat spinal cord incubated with specifi c COX-2 antiserum showed intense COX-2-like immunoreactivity (COX-2-li ) in the superficial dorsal horn of the spinal cord (laminae I and II) and around the central canal (lamina X). COX-2-li was also observed i n some neurones in deep dorsal horn and in individual motor neurones i n ventral horn. COX-2-li was not observed in the cell bodies of DRG. 6 Superfusion of the lumbar spinal cord of normal rats with artificial CSF and subsequent radioimmunoassay revealed the presence of prostagla ndin D-2 (PGD(2))< PGE(2), but not PGI(2) (determined by measurement o f the stable metabolite, 6-keto-PGF(1 alpha)) or PCF2 alpha. 7 These d ata suggest that eicosanoids synthesized by an active COX pathway in t he spinal cord of normal animals may contribute to nociceptive process ing, but only when the spinal cord neurones are rendered hyperexcitabl e following C-fibre stimulation. Selective inhibition of one or both o f the COX isoforms in normal animals may represent a novel target for spinal analgesia.