Mirogabalin is a novel α2δ ligand approved in Japan for the treatment of peripheral neuropathic pain. However, the sites of action of α2δ ligands to produce analgesic effects on inflammatory pain remain unclear. In this study, we investigated the analgesic effect and site of action of mirogabalin using the rat formalin test, an acute inflammatory pain model. Mirogabalin was administered orally, intrathecally, and intracerebroventricularly. Open field tests were performed to evaluate the effect of oral-, intrathecally, and intracerebroventricularly administered mirogabalin on locomotor activity and orientation ability. Oral mirogabalin produced an analgesic effect when the formalin test was performed 4 h, but not 1 or 2 h, after oral administration. Intrathecal, but not intracerebroventricular, administration of mirogabalin produced analgesic effects when mirogabalin was administered 10 min before formalin injection. These analgesic effects were not antagonized by idazoxan, an α2 adrenergic antagonist; WAY100135, a 5-HT1A antagonist; or naloxone, an opioid receptor antagonist. Mirogabalin attenuated moving distances 1 and 2 h after oral administration and 10 min after intracerebroventricular administration, but not 10 min after intrathecal administration. In the oral administration group, the time course of the analgesic effect was different from that of moving distance. In the intracerebroventricular group, mirogabalin attenuated moving distances but did not produce an analgesic effect. In the intrathecal group, mirogabalin produced an analgesic effect but did not affect moving distances. These findings suggest that the analgesic effect of mirogabalin on the rat formalin test is mediated by spinal action and not by the activation of α2, 5-HT1A, or opioid receptors, and that the inhibitory effect of mirogabalin on moving distances is mediated by the supraspinal brain.
Excellent outcomes were achieved with spinal cord stimulation (SCS) for 7 to 10 days on 2 patients who developed postherpetic neuralgia. Both patients were within 2 to 3 months of the onset of the condition, and nerve blocks provided only temporary pain relief and drug therapies had poor efficacy. The authors believe that limited-duration SCS for subacute postherpetic neuralgia is a useful treatment approach that may prevent the pain from progressing to chronic postherpetic neuralgia. Key words: Spinal sensitisation, Subacute postherpetic neuralgia
Background and Purpose Morphine induces spinal 5-hydroxytryptamine (5-HT) release, but the role and mechanism of this release is unclear. The purpose of this study was to define the role and mechanism of spinal 5-HT release induced by oral morphine. We also examined whether persistent pain affected the oral morphine-induced spinal release of 5-HT. Experimental Approach Spinal 5-HT release was measured using microdialysis in lumbar cerebrospinal fluid (CSF). Two opioids, morphine and oxycodone, were orally administered and 5-HT release was measured in awake rats. Naloxone was used to determine whether the effect of morphine on 5-HT release was mediated by opioid receptor activation. To study persistent pain, the formalin test was used. Forty-five minutes after oral morphine, the formalin test was started and spinal 5-HT release was measured. Key Results Oral morphine, but not oral oxycodone, increased 5-HT release in the spinal cord to approximately 4,000% of the baseline value, and this effect of morphine was not antagonised by naloxone at the dose that antagonised the analgesic effect of morphine. Formalin-induced persistent pain itself had no effect on spinal 5-HT release but enhanced the oral morphine-induced spinal 5-HT release. Conclusion and Implications Oral morphine-induced spinal 5-HT release is not mediated by opioid receptor activation. Spinal 5-HT release induced by oral morphine does not play an important role in the analgesic effect of morphine. Persistent pain increases oral morphine-induced spinal 5-HT release.
Morphine induces spinal 5‐hydroxytryptamine (5‐HT) release, but the role and mechanism of the spinal 5‐HT release induced by morphine are not well understood. The purpose of this study was to define the role and mechanism of spinal 5‐HT release induced by oral morphine. We also examined whether persistent pain affected the spinal 5‐HT release induced by oral morphine. Spinal 5‐HT release was measured using microdialysis of lumbar cerebrospinal fluid (CSF). Two opioids, morphine and oxycodone, were orally administered and 5‐HT release was measured in awake rats. Naloxone and β‐funaltrexamine (β‐FNA) were used to determine whether the effect of morphine on 5‐HT release was mediated by opioid receptor activation. To study persistent pain, a formalin test was used. At 45 min after oral morphine administration, the formalin test was started and spinal 5‐HT release was measured. Oral morphine, but not oral oxycodone, increased 5‐HT release at the spinal cord to approximately 4000% of the baseline value. This effect of morphine was not antagonized by either naloxone or β‐FNA at a dose that antagonized the antinociceptive effect of morphine. Formalin‐induced persistent pain itself had no effect on spinal 5‐HT release but enhanced the oral morphine‐induced spinal 5‐HT release. Oral morphine‐induced spinal 5‐HT release was not mediated by opioid receptor activation. Spinal 5‐HT induced by oral morphine did not play a major role in the antinociceptive effect of morphine in the hot plate test. Persistent pain increased oral morphine‐induced spinal 5‐HT release.
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