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...

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To assess effects of stimulus intensity, dose-response curves in rats for radiant heat-evoked withdrawal of the hind paw was assessed after the intrathecal (i.t.) injection of sufentanil and morphine, mu-opioid agonists differing in intrinsic activity, at Low, Medium, and High stimulus intensities. Baseline latencies observed at the 3 intensities were: low = +/- 0.3; medium = 8.9 +/- 0.2; high = 5.7 +/- 0.1 sec. After i.t. administration of sufentanil or morphine, there was a right shift in the dose-response curves with morphine exhibiting a greater magnitude right shift than that of sufentanil. Dose ratios (ED 50 Medium/ED 50 Low and ED 50 High/ED 50 Low) with 95% CI for sufentanil were, respectively, 2.5 (2.2-2.9) and 7.7 (6.7-8.9), and the dose ratio for morphine (ED 50 Medium/ED 50 Low) was 34 (28-41). At the highest intensity, due to a plateau in the morphine dose-response curve, ED 50 and dose ratio calculations could not be performed. The present study supports the pharmacological model of receptor occupancy, such that the higher efficacy receptor agonist, sufentanil, demonstrated a lesser magnitude right shift than the lower efficacy agonist, morphine, while at the high stimulus intensity, morphine but not sufentanil, was a partial agonist.