Novel insight into TRPV1-induced mitochondrial dysfunction in neuropathic pain.

Neuropathic pain remains one of the leading causes of global disability. The mechanism of neuropathic pain development and maintenance involves mitochondrial dysfunction induced-neuronal apoptosis of peripheral and central nociceptive pathways. The TRPV1 is a non-selective cation channel, which has a high Ca2+ permeability, playing an essential role in neuronal apoptosis in the spinal cord following peripheral nerve injury. However, the mechanism of how TRPV1 activation in the spinal cord induces mitochondrial dysfunction-mediate neuronal apoptosis, resulting in allodynia is unknown. Here, we found that activating the TRPV1 channel in the spinal cord using capsaicin, a TRPV1 agonist, results in mechanical and thermal hypersensitivity that were found to be mediated by neuroinflammation, elevated level of apoptosis, and a reduction in transcription of the mitochondrial complexes in the spinal cord and DRG. Moreover, during the early activation of the TRPV1 (1h, 24h, 48h following the capsaicin injection in the spinal cord) we observed a robust reduction in mitochondrial oxygen consumption in the non-phosphorylated state, ATP-linked respiration, maximal respiration, and electron transfer capacity (ETC). A more advanced experiment, wherein we controlled capsaicin, Ca2+ concentration and the exposure time in isolated spinal cord tissue (Lumbar, L1-L6), unveiled that TRPV1 activation impairing the mitochondrial function in terms of oxygen consumption, collapsing the Ψm and induction of the mitochondrial permeability transition pore (mPTP), which were reversed by the mPTP inhibitor-Cyclosporin A (CsA) during challenging the mitochondria with Ca2+ in a dose-dependent manner. More critically, injection of TRPV1 antagonist AMG9810 in the spinal cord following sciatic nerve crush reversed mechanical allodynia and modulated thermal hypersensitivity. In addition, the presence of TRPV1 antagonist-AMG9810 along with capsaicin and Ca2+ during challenging the spinal cord tissue completely prevents the early mPTP induction, the reduction in oxygen consumption and. In conclusion, our findings suggest that TRPV1 activation induces neuronal apoptosis, neuroinflammation, and mitochondrial dysfunction in the spinal cord, reflected in mechanical and thermal allodynia. Notable, the mitochondrial dysfunction following the TRPV1 activation in the spinal cord includes crucial elements that contribute to neuronal death, including mPTP induction, reduction in Ψm and oxygen consumption. Strikingly, regulating the TRPV1 following sciatic nerve injury reverses hypersensitivity probably via protection of the mitochondrial, suggesting a fundamental role for the TRPV1 pathway in mitochondrial dysfunction-mediated pain development.