The antinociceptive effect of reversible monoamine oxidase-A inhibitors in a mouse neuropathic pain model

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Abstract

Neuropathic pain is a debilitating condition that is often resistant to common analgesics, such as opioids, but is sensitive to some antidepressants, an effect that seems to be mediated by spinal cord 5-HT3 receptors. Because the analgesic potential of monoamine oxidase-A (MAO-A) inhibitors is understudied, we evaluated the potential antinociceptive effect of the reversible MAO-A inhibitors moclobemide and 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in a mouse neuropathic pain model induced by chronic constriction injury (CCI) of the sciatic nerve. Neuropathic mice showed a decreased mechanical paw withdrawal threshold (PWT) 7 days after lesion compared with the baseline PWT, characterizing the development of hyperalgesia. Moclobemide (100–300 μmol/kg, s.c.) and 2-DMPI (30–300 μmol/kg, s.c.) treatments were able to reverse the CCI-induced hyperalgesia, with 50% inhibitory dose (ID50) values of 39 (18–84) and 11 (4–33) μmol/kg, and maximum inhibition (Imax) values of 88 ± 14 and 98 ± 15%, respectively, at the 300 μmol/kg dose. In addition, we observed a significant increase in the MAO-A activity in the lumbar spinal cord of CCI-submitted mice compared with sham-operated animals. Furthermore, the antihyperalgesic effects of both 2-DMPI and moclobemide were largely reversed by intrathecal injection of the 5-HT3 receptor antagonist ondansetron (10 μg/site). These results suggest a possible involvement of MAO-A in the mechanisms of neuropathic pain and a potential utility of the reversible inhibitors of MAO-A in the development of new therapeutic approaches to treat it.

Highlights

▪ Chronic neuropathy caused an increase in the MAO-A activity in the spinal cord. ▪ Reversible MAO-A inhibitors presented an antinociceptive effect in neuropathic mice. ▪ The antinociceptive effect of MAO-A inhibitors was mediated by spinal 5-HT3 receptors.

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