Involvement of TRPV1 and MOR-NMDAR complex on the antiallodynic effect of LMH-2, a sigma-1 receptor antagonist, in mouse model of diabetic neuropathy - a behavioral approach

TL;DR

This study shows that LMH-2, a sigma-1 receptor antagonist, reduces neuropathic pain in diabetic mice, likely through TRPV1 and partial interaction with the MOR-NMDAR complex.

Contribution

The study identifies TRPV1 as a key player in LMH-2's antiallodynic effect and explores its limited interaction with the MOR-NMDAR complex in diabetic neuropathy.

Findings

Capsazepine blocked LMH-2's antinociceptive effect, suggesting TRPV1 involvement.

NMDA reduced LMH-2's antiallodynic effect, but naloxone did not.

Molecular docking supports a potential interaction between LMH-2 and TRPV1.

Abstract

Recently, the antinociceptive effect of LMH-2, a σ1 receptor antagonist, has been reported in diabetic mice with neuropathic pain. However, the mechanism by which this effect is produced is not completely clear. In this study, we explored the involvement of TRPV1 and the MOR-NMDAR complex in the antiallodynic effect of LMH-2 in hyperglycemic mice with neuropathic pain.

Hyperglycemia was induced in mice by administering streptozotocin-nicotinamide. Four weeks later, once neuropathic pain was established, the antiallodynic effect of LMH-2 (56.2 mg/kg) was evaluated using the up-down method with the von Frey filaments, both in the absence and the presence of capsazepine (8 mg/kg, ip), naloxone (NLX, 1 mg/kg, ip), NMDA (0.4 nM/10 µL, it), or their co-administration (NLX-NMDA). Gabapentin was used as positive control.

Pretreatment with NLX did not alter the antiallodynic effect of LMH-2 in the up-down method with the von Frey filaments in hyperglycemic mice, whereas NMDA significantly reduced it. The addition of NLX to NMDA (NLX-NMDA) did not modify the effect of NMDA alone on the antiallodynic activity of LMH-2. Additionally, capsazepine completely blocked the antinociceptive effect of LMH-2 in hyperglycemic mice. Molecular docking analysis suggested a potential interaction between LMH-2 and TRPV1. Moreover, a higher dose of LMH-2 did not cause mortality or damage in healthy mice.

These results suggest the potential utility of LMH-2 in the treatment of diabetic neuropathy and highlight a key role for TRPV1 in LMH-2’s antiallodynic mechanism, along with a possible, albeit limited, interaction with the MOR/NMDA complex.

The online version contains supplementary material available at 10.1007/s43440-025-00727-4.

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