Prostanoids synthesized by cyclo‐oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability

Abstract

1 The responses of wide dynamic range spinal dorsal horn neurones to noxious mechanical stimulation of the ankle or knee joint were tested before and after spinal administration of the non-selective cyclooxygenase (COX) inhibitors, indomethacin and meclofenamic acid. Neither of these drugs altered the responses of these neurones to noxious mechanical stimulation. 2 Wind-up of a spinal nociceptive re¯ex evoked by electrical stimulation of the sural nerve at C-®bre strength was dose-dependently inhibited by intravenous administration of indomethacin, a non-selective COX inhibitor, and SC58125, a selective COX-2 inhibitor. Intrathecal administration of indomethacin also reduced the wind-up of this nociceptive re¯ex. 3 Western blot analysis of proteins extracted from normal rat spinal cord revealed the presence of both cyclo-oxygenase (COX)-1 and COX-2 proteins. 4 Immunocytochemistry of sections of normal rat spinal cord with speci®c COX-1 antiserum revealed little speci®c COX-1-like immunoreactivity in the grey matter. With the same antiserum, intense COX-1-like immunoreactivity was observed in the cytoplasm, nuclear membrane and axonal processes of small to medium sized (51000 mm 2 ) dorsal root ganglion (DRG) cell bodies. 5 Immunocytochemistry of sections of normal rat spinal cord incubated with speci®c COX-2 antiserum showed intense COX-2-like immunoreactivity (COX-2-li) in the super®cial dorsal horn of the spinal cord (laminae I and II) and around the central canal (lamina X). COX-2-li was also observed in some neurones in deep dorsal horn and in individual motor neurones in 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 arti®cial CSF and subsequent radioimmunoassay revealed the presence of prostaglandin D 2 (PGD 2 )5PGE 2 , but not PGI 2 (determined by measurement of the stable metabolite, 6-keto-PGF 1a ) or PGF 2a . 7 These data suggest that eicosanoids synthesized by an active COX pathway in the spinal cord of normal animals may contribute to nociceptive processing, but only when the spinal cord neurones are rendered hyperexcitable following C-®bre stimulation. Selective inhibition of one or both of the COX isoforms in normal animals may represent a novel target for spinal analgesia.

Peripheral inflammatory hyperalgesia depends on the COX increase in the dorsal root ganglion

“…However, we found that the expression of COX2 was significantly higher than that of COX-1. Importantly, although the constitutive expression of COX-1 in DRG cells has been previously detected by different techniques, such as in situ hybridization (24), Northern blotting (25)(26)(27), immunohistochemistry (8,26), and Western blotting (8,26,28), there is little data demonstrating the constitutive expression of COX-2 in DRG cells (23).…”

“…The isoform of COX constitutively expressed in dorsal root ganglion (DRG) is still unclear. Although COX-1 mRNA and, to a lesser extent, COX-2 mRNA have been detected in DRG cultures (7) under basal conditions, immunohistochemical studies have shown that DRG cells express only COX-1, but not COX-2 protein (8), in contrast to the spinal cord cells that express COX-2 but not COX-1, protein (8). These data suggest a specific role for each COX isoform under normal conditions in the nervous system.…”

Nociception in cyclooxygenase isozyme-deficient mice

“…All sensory pathways synapse in the dorsal horn of the spinal cord, and most have synapses in the thalamus and periaqueductal gray matter of the midbrain. COX-1 and COX-2 both have been identified in the brain and spinal cord of humans and rats; COX-2, as well as COX-1, is constitutively expressed (12)(13)(14). It is likely, therefore, that PGs made by both COX enzymes are involved in hyperalgesia.…”

TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

“…These early experiments and the subsequent findings that TRPA1 is activated by electrophilic compounds 4,5 led us to speculate that p-AP and APAP indirectly activate TRPA1 on primary sensory neurons, after their conversion to electrophilic compounds such as p-benzoquinone (p-BQ) and N-acetyl-p-benzoquinoneimine (NAPQI). The formation of these electrophilic compounds in vivo is catalysed by several enzymes, including cytochrome P450 (CYP450) monoxygenases, peroxidases and COX, many of which are present in the central nervous system [19][20][21][24][25][26][27][28][29] . NAPQI is believed to mediate the well-known hepato-and nephro-toxic effects of APAP.…”