Duloxetine, a selective but balanced serotonergic and noradrenergic reuptake inhibitor, was evaluated in the acute nociceptive pain models of tail flick and hot plate in mice and in the persistent and/or inflammatory pain models of acetic acidinduced writhing in mice, carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats, and capsaicin-induced mechanical allodynia in rats. In acute pain models, duloxetine had no significant effect on response latency in the mouse tail-flick test but produced modest increases in response latencies in the mouse hot plate test. Morphine produced dose-related analgesic effects in both the mouse tailflick and hot plate tests. In models of inflammatory and/or persistent pain, duloxetine, morphine, and ibuprofen produced dose-related decreases in acetic acid-induced writhing in mice. Duloxetine, ibuprofen, and gabapentin also produced dosedependent reversals of both thermal hyperalgesia and mechanical allodynia produced by carrageenan in rats. In addition, both duloxetine and morphine produced a significant reduction of capsaicin-induced mechanical allodynia in rats. Duloxetine and gabapentin were without substantial effect on the Rotorod test in mice, whereas morphine and ibuprofen produced a significant impairment. Our data indicate that duloxetine may be efficacious in the treatment of persistent and/or inflammatory pain states at doses that have modest or no effect on acute nociception or motor performance.Descending pain inhibitory circuits contribute to the supraspinal control of spinal transmission of nociceptive information. Descending inhibitory circuits include not only the neuronal connections between the ventrolateral periaqueductal gray and rostral ventral medulla but also the dorsolateral pontine tegmentum, areas that in turn project to the spinal cord dorsal horn lamina (e.g., for review, see Fields and Basbaum, 1994). The rostral ventral medulla is a primary source of serotonergic input to the spinal cord, whereas the dorsolateral pontine tegmentum (particularly the A7 and A5 adrenergic cell groups) is a source of noradrenergic input to the spinal cord. Accordingly, the serotonergic and noradrenergic systems have been implicated in the descending inhibitory control of pain in humans and animals (e.g., Fields et al., 1991). For example, the analgesia produced by the injection of morphine into the periaqueductal gray was antagonized only by a combination of serotonergic and noradrenergic antagonists administered intrathecally (Yaksh, 1979). More recently, antidepressant drugs with serotonergic or noradrenergic reuptake inhibition have been reported to produce varying degrees of pain relief in several persistent, or chronic, pain syndromes in humans, including diabetic neuropathy (Max et al., 1992;Sindrup and Jensen, 1999), postherpetic neuralgia (e.g., Kishore-Kumar et al., 1990;Max et al., 1988), and fibromyalgia (Goldenberg et al., 1996;Rani et al., 1996). In addition, antidepressant drugs that inhibit serotonin and/or norepinephrine reuptake...
