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

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.

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system

“…We then evaluated the effect of chronic fisetin treatment on the MAO-A and MAO-B activities in mouse spinal cord. As shown in Table 2, the activity of MAO-A but not MAO-B increased markedly when the mice were rendered neuropathic by CCI-lesion, which is in congruent with a recent study by Villarinho et al31. Chronic treatment of CCI mice with fisetin (5, 15 and 45 mg/kg) dose-dependently inhibited the escalated spinal MAO-A activity, and the MAO-A activity is reduced to levels observed in non-injured animals following the treatment with fisetin at the dose of 45 mg/kg.…”

Isorhynchophylline Exerts Antinociceptive Effects on Behavioral Hyperalgesia and Allodynia in a Mouse Model of Neuropathic Pain: Evidence of a 5-HT1A Receptor-Mediated Mechanism

“…We then evaluated the spinal MAO-A and MAO-B activities following repetitively oral isorhynchophylline treatment. As shown in Table 1, Neuropathic mice showed escalated activity of MAO-A but not MAO-B compared with sham mice, which is consistent with a previous study by Villarinho et al (2013). Following repetitive oral treatment, isorhynchophylline with doses ranging from 5 to 45 mg/kg dose-dependently inhibited the escalated spinal MAO-A activity in neuropathic mice (F 3,38 = 14.2, p = 0.0072), and at the high dose of 45 mg/kg the MAO-A activity is reduced to the level essentially equivalent to that of sham mice.…”

Monoamine Oxidase Inhibitors—Revisiting a Therapeutic Principle

“…Several studies investigated the effects of MAO inhibitors on neuropathic pain (Apaydin et al, 2001;Villarinho et al, 2013;Villarinho et al, 2012). Moclobemide was investigated in rats (Apaydin et al, 2001) and mice (Villarinho et al, 2013) which showed an increased mechanical paw withdrawal threshold and both studies concluded that moclobemide might be a treatment alternative for symptoms of peripheral neuropathic conditions.…”

“…Moclobemide was investigated in rats (Apaydin et al, 2001) and mice (Villarinho et al, 2013) which showed an increased mechanical paw withdrawal threshold and both studies concluded that moclobemide might be a treatment alternative for symptoms of peripheral neuropathic conditions. In the mouse model, the same authors applied the MAO-B inhibitor selegiline on postoperative and neuropathic pain and concluded that MAO-B exerts a critical role in the development in these pain conditions.…”