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Intravenous lidocaine administration produces an analgesic effect in various pain states, such as neuropathic and acute pain, although the underlying mechanisms remains unclear. Here, we hypothesized that intravenous lidocaine acts on spinal cord neurons and induces analgesia in acute pain. We therefore examined the action of intravenous lidocaine in the spinal cord using the in vivo patch-clamp technique. We first investigated the effects of intravenous lidocaine using behavioural measures in rats. We then performed in vivo patch-clamp recording from spinal substantia gelatinosa (SG) neurons. Intravenous lidocaine had a dose-dependent analgesic effect on the withdrawal response to noxious mechanical stimuli. In the electrophysiological experiments, intravenous lidocaine inhibited the excitatory postsynaptic currents (EPSCs) evoked by noxious pinch stimuli. Intravenous lidocaine also decreased the frequency, but did not change the amplitude, of both spontaneous and miniature EPSCs. However, it did not affect inhibitory postsynaptic currents. Furthermore, intravenous lidocaine induced outward currents in SG neurons. Intravenous lidocaine inhibits glutamate release from presynaptic terminals in spinal SG neurons. Concomitantly, it hyperpolarizes postsynaptic neurons by shifting the membrane potential. This decrease in the excitability of spinal dorsal horn neurons may be a possible mechanism for the analgesic action of intravenous lidocaine in acute pain.

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Opioid usage for pain therapy is limited by its undesirable clinical effects, including paradoxical hyperalgesia, also known as opioid-induced hyperalgesia (OIH). However, the mechanisms associated with the development and maintenance of OIH remain unclear. Here, we investigated the effect of serotonin inhibition by the 5-HT 3 receptor antagonist, ondansetron (OND), as well as serotonin deprivation via its synthesis inhibitor para-chlorophenylalanine, on mouse OIH models, with particular focus on astrocyte activation. Co-administering of OND and morphine, in combination with serotonin depletion, inhibited mechanical hyperalgesia and astrocyte activation in the spinal dorsal horn of mouse OIH models. Although previous studies have suggested that activation of astrocytes in the spinal dorsal horn is essential for the development and maintenance of OIH, herein, treatment with carbenoxolone (CBX), a gap junction inhibitor that suppresses astrocyte activation, did not ameliorate mechanical hyperalgesia in mouse OIH models. These results indicate that serotonin in the spinal dorsal horn, and activation of the 5-HT 3 receptor play essential roles in OIH induced by chronic morphine, while astrocyte activation in the spinal dorsal horn serves as a secondary effect of OIH. Our findings further suggest that serotonergic regulation in the spinal dorsal horn may be a therapeutic target of OIH. Perspective: The current study revealed that the descending serotonergic pain-facilitatory system in the spinal dorsal horn is crucial in OIH, and that activation of astrocytes is a secondary phenotype of OIH. Our study offers new therapeutic targets for OIH and may help reduce inappropriate opioid use.

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