Mitochondrial dysfunction in the spinal cord contributes to peripheral hypersensitivity in a nitroglycerin-induced migraine model

Mitochondrial dysfunction was reported as a potential factor that contributes to the development of migraine and peripheral hypersensitivity. The recent accumulation of knowledge on mitochondrial involvement in migraine paved the way for a new non-pharmacological-therapeutic strategy like hyperbaric oxygen therapy (HBOT), which targets mitochondrial dysfunction. Yet, the efficacy of HBOT in modaulting migraine associated pain remains unclear. Rats were injected with nitroglycerin (NTG, 10 mg/kg), a human migraine trigger, every other day for 9 days. Mechanical and thermal sensitivity, motor function, anxiety and depression-like behavior, and cognitive function were measured following chronic NTG treatment. The HBOT (2.5 ATA) was performed immediately after NTG injection and twice daily (12-hour intervals) for ten consecutive days. In order to assess mitochondrial function in the spinal cord (L1-L6), high-resolution respirometry was measured on day 12 using the OROBOROS-O2k. In addition, RT-PCR was performed at the end of the experiment to assess neuroinflammation and neuromodulation in the brain region involved in sensory and pain, including the trigeminal nucleus caudalis (TNC), hippocampus (HPC), somatosensory cortex (SSC), and amygdala (Amg). The current result shows that chronic NTG treatment induces peripheral hypersensitivity (mechanical and thermal) without affecting motor and cognitive function. In addition, the NTG-treated group exhibits increased anxiety- and depression-like behaviors compared to the vehicle group. Furthermore, NTG treatment leads to changes in the expression of the pro-inflammatory cytokine marker (IL6), neuropeptides (CGRP) and neuronal activation marker (cFOS) in the brain region involved in pain processing (SSC, TNC, HPC, Amg). Moreover, mitochondrial dysfunction in terms of oxygen consumption was observed in the spinal cord (L1-L6) following chronic NTG treatment. In contrast, HBOT during NTG treatment attenuated the development of peripheral hypersensitivity and improved both neuroinflammation and mitochondrial function. Our findings indicate that chronic treatment of the human migraine trigger (NTG) leads to peripheral hypersensitivity development, depression and anxiety-like behavior, these effects were reversed by HBOT, probably by alleviating neuroinflammation and mitochondrial function in the CNS. Taken together, the current findings underscore the fact that HBOT has anti-inflammatory and neuroprotective effects that modulate the development of NTG-induced peripheral hypersensitivity.