The Acute Antihyperalgesic Action of Nonsteroidal, Anti-Inflammatory Drugs and Release of Spinal Prostaglandin E₂Is Mediated by the Inhibition of Constitutive Spinal Cyclooxygenase-2 (COX-2) but not COX-1

Abstract

Western blots show the constitutive expression of COX-1 and COX-2 in the rat spinal dorsal and ventral horns and in the dorsal root ganglia. Using selective inhibitors of cyclooxygenase (COX) isozymes, we show that in rats with chronic indwelling intrathecal catheters the acute thermal hyperalgesia evoked by the spinal delivery of substance P (SP; 20 nmol) or NMDA (2 nmol) and the thermal hyperalgesia induced by the injection of carrageenan into the paw are suppressed by intrathecal and systemic COX-2 inhibitors. The intrathecal effects are dosedependent and stereospecific. In contrast, a COX-1 inhibitor given systemically, but not spinally, reduced carrageenanevoked thermal hyperalgesia but had no effect by any route with spinal SP hyperalgesia. Using intrathecal loop dialysis catheters, we showed that intrathecal SP would enhance the release of prostaglandin E 2 (PGE 2 ). This intrathecally evoked release of spinal PGE 2 was diminished by systemic delivery of nonspecific COX and COX-2-selective inhibitors, but not a COX-1-selective inhibitor. Given at systemic doses that block SP-and carrageenan-evoked hyperalgesia, COX-2, but not COX-1, inhibitors reduced spinal SP-evoked PGE 2 release. Thus, constitutive spinal COX-2, but not COX-1, is an important contributor to the acute antihyperalgesic effects of spinal as well as systemic COX-2 inhibitors.Key words: cyclooxygenase inhibitor; intrathecal injection; thermal hyperalgesia; NK-1; substance P; NMDA; ibuprofen; Tissue injury results in a heightened sensitivity to subsequent noxious input (hyperalgesia). In behavioral models of injuryinduced hyperalgesia, nonsteroidal, anti-inflammatory drugs (NSAIDs) normalize the otherwise sensitized pain thresholds . Early work showed that systemically delivered NSAIDs were effective inhibitors of cyclooxygenase (COX) (Smith and Willis, 1971;Vane, 1971) and that peripheral prostanoids could sensitize the peripheral terminal. This suggested that hyperalgesia arose from a peripheral afferent sensitization.Tissue injury also evokes persistent afferent traffic that initiates a spinal sensitization. Studies on the pharmacology of this sensitization using intrathecal drug delivery indicate that the hyperalgesia results in part from a complex cascade starting with the activation of spinal neurokinin-1 (NK-1) and NMDA receptors secondary to the spinal release of substance P (SP) and glutamate. Among several elements, this cascade activates spinal phospholipases and generates prostanoids by spinal COX , leading to spinal prostanoid release (Yang et al., 1996a,b;Willingale et al., 1997;Ebersberger et al., 1999). The hyperalgesic effects (Yaksh, 1982; Malmberg and Yaksh, 1992a,b) and the spinal release of prostaglandins (Malmberg and Yaksh, 1995a,b) are diminished by spinal COX inhibitors at doses that have no systemic action. Consistent with the hypothesized spinal organization, intrathecal SP and NMDA, in the absence of tissue injury, induce a transient thermal hyperalgesia (Malmberg and Yaksh, 1992b;Dirig and Yaksh, 1996) and an...

Role of neurokinin type 1 receptor in nociception at the periphery and the spinal level in the rat

“…40 One of the mechanisms of nociception following intrathecal SP is to promote prostaglandin E2 synthesis in a NK1r-dependent manner, and this could be blocked by nonspecific COX inhibitor or COX-2 inhibitor or even by inhibiting calcium-dependent phospholipase A2. [40][41][42] In the current study, combining i.t. and i.w.…”

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

“…Consequently, involvement of 5␣-DHP and 3␣,5␣-THP biosynthetic pathways in the regulation of nociception needs to be considered in regard to various neurobiological mechanisms occurring in both acute and chronic phases of pain, even though in vivo studies have shown that 3␣,5␣-THP and its synthetic analogs induce antinociceptive effects in rats and humans (40-43). It is also important to recall that rNK1-mediated hyperalgesia seems to be an extremely complex mechanism involving the release of prostanoids (44,45) and glutamate (46,47), and the phosphorylation of NMDA receptor through a protein kinase C transduction process (48,49). Therefore, we suggest here an hypothetical model to recapitulate and clarify neurochemical events that may occur in spinal Values are the mean Ϯ SEM of four independent experiments.…”

Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes

“…These data indicate that the onset of formalin hyperalgesia and of upregulated spinal COX-2 activity and protein in diabetic rats occur in parallel, and this prompted us to investigate a possible causal link between elevated spinal COX-2 and formalin hyperalgesia. To do this, we pretreated the spinal cord of diabetic rats with indomethacin or SC-58125, using intrathecal drug doses shown to alleviate hyperalgesia in rats (11,17). Both drugs attenuated exaggerated paw flinching during phase II of the test, indicating that hyperalgesia to paw formalin injection in diabetic rats is spinally mediated and at least partly due to activity of the COX-2 isozyme.…”