Sciatic nerve stimulation alleviates acute neuropathic pain via modulation of neuroinflammation and descending pain inhibition in a rodent model

Abstract

Background Neuropathic pain (NP) is characterized by abnormal activation of pain conducting pathways and manifests as mechanical allodynia and thermal hypersensitivity. Peripheral nerve stimulation is used for treatment of medically refractory chronic NP and has been shown to reduce neuroinflammation. However, whether sciatic nerve stimulation (SNS) is of therapeutic benefit to NP remains unclear. Moreover, the optimal frequency for SNS is unknown. To address this research gap, we investigated the effect of SNS in an acute NP rodent model. Methods Rats with right L5 nerve root ligation (NRL) or Sham surgery were used. Ipsilateral SNS was performed at 2 Hz, 20 Hz, and 60 Hz frequencies. Behavioral tests were performed to assess pain and thermal hypersensitivity before and after NRL and SNS. Expression of inflammatory proteins in the L5 spinal cord and the immunohistochemical alterations of spinal cord astrocytes and microglia were examined on post-injury day 7 (PID7) following NRL and SNS. The involvement of the descending pain modulatory pathway was also investigated. Results Following NRL, the rats showed a decreased pain threshold and latency on the von Frey and Hargreaves tests. The immunofluorescence results indicated hyperactivation of superficial spinal cord dorsal horn (SCDH) neurons. Both 2-Hz and 20-Hz SNS alleviated pain behavior and hyperactivation of SCDH neurons. On PID7, NRL resulted in elevated expression of spinal cord inflammatory proteins including NF-κB, TNF-α, IL-1β, and IL-6, which was mitigated by 2-Hz and 20-Hz SNS. Furthermore, 2-Hz and 20-Hz SNS suppressed the activation of spinal cord astrocytes and microglia following NRL on PID7. Activity of the descending serotoninergic pain modulation pathway showed an increase early on PID1 following 2-Hz and 20-Hz SNS. Conclusions Our results support that both 2-Hz and 20-Hz SNS can alleviate NP behaviors and hyperactivation of pain conducting pathways. We showed that SNS regulates neuroinflammation and reduces inflammatory protein expression, astrocytic gliosis, and microglia activation. During the early post-injury period, SNS also facilitates the descending pain modulatory pathway. Taken together, these findings support the therapeutic potential of SNS for acute NP.

A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain

“…This was explained by the reduction in spinal cord inflammatory proteins (NF-κB, TNF-α, IL-1β, and IL-6) as well as the inhibition of astrocytes and microglia. Furthermore, neuromodulation therapy increased the activation of the analgesic descending serotoninergic pathway [ 106 ]. Finally, in mice with SNI, TENS stimulation (100 HZ) led to decreased hyperalgesia by inhibiting glial activation, MAP kinase activation, PKC-γ, and p-cyclic-AMP response element binding (CREB) expression, and proinflammatory cytokines, with an additional increase in spinal cord opioid receptors [ 47 ], thus providing insights into how neuromodulation therapies applied on DRGs and related spinal nerves can reduce neuropathic pain.…”

“…In turn, dorsal horn neurons also release neurotransmitters and neuropeptides that participate in the maintenance and potentiation of nociceptive signaling, as well as neuronal plasticity [ 112 ]. It is believed that neuromodulation therapies in the spinal cord may decrease glial cell activity, as classical markers of these non-neuronal cells decreased upon neuromodulation interventions [ 47 , 90 ], and consequently, NF-κB activation and levels of downstream inflammatory molecules, including TNF-α, IL-1β, and IL-6, are also reduced [ 106 ]. Neuromodulation therapies can also directly reduce neuronal activity in both the brain [ 91 ] and the spinal cord.…”

Ferroptosis: a new regulatory mechanism in neuropathic pain

“…Neuropathic pain (NP) is a pain syndrome resulting from injury to the peripheral or central nervous system ( Chen et al, 2011 ). It is characterized by mechanical abnormal pain and thermal nociceptive hypersensitivity ( Wong et al, 2022 ). Neuropathic pain is experienced by 6.9–10% of the world’s population ( Pickering et al, 2017 ).…”

The role of walking exercise on axonal regrowth and neuropathic pain markers in dorsal root ganglion after sciatic nerve injury

“…Damage to the sciatic nerve, a peripheral nerve in the lower human body, can result from conditions like traumatic nerve injury, nerve inflammation, and strenuous sports activities, leading to neuropathic pain (NP) and mechanical allodynia ( Finnerup et al, 2021 ; Wong et al, 2022 ). NP is a well-known and very complex type of pain caused by traumatic nerve injury and dysfunction in the nervous system.…”