Spinal Cord Stimulation Attenuates Mechanical Allodynia and Increases Central Resolvin D1 Levels in Rats With Spared Nerve Injury

Abstract

Mounting evidence from animal models of inflammatory and neuropathic pain suggests that inflammation regulates the resolution of pain by producing specialized pro-resolving mediators (SPMs), such as resolvin D1 (RvD1). However, it remains unclear how SPMs are induced in the central nervous system and whether these mechanisms can be reconciled with outcomes of neuromodulation therapies for pain, such as spinal cord stimulation. Here, we show that in a male rat model of neuropathic pain produced by spared nerve injury (SNI), 1 kHz spinal cord stimulation (1 kHz SCS) alone was sufficient to reduce mechanical allodynia and increase RvD1 in the cerebrospinal fluid (CSF). SNI resulted in robust and persistent mechanical allodynia and cold allodynia. Spinal cord electrode implantation was conducted at the T11-T13 vertebral level 1 week after SNI. The spinal locations of the implanted electrodes were validated by X-Ray radiography. 1 kHz SCS was applied for 6 h at 0.1 ms pulse-width, and this stimulation alone was sufficient to effectively reduce nerve injury-induced mechanical allodynia during stimulation without affecting SNI-induced cold allodynia. SCS alone significantly reduced interleukin-1β levels in both serum and CSF samples. Strikingly, SCS significantly increased RvD1 levels in the CSF but not serum. Finally, intrathecal injection of RvD1 (100 and 500 ng, i.t.) 4 weeks after nerve injury reduced SNI-induced mechanical allodynia in a dose-dependent manner. Our findings suggest that 1 kHz SCS may alleviate neuropathic pain via reduction of IL-1β and via production and/or release of RvD1 to control SNI-induced neuroinflammation.

Impaired muscarinic modulation of the rat prelimbic cortex in neuropathic pain is sexually dimorphic and associated with cold allodynia

“…Intrathecal injection of adipose tissue-derived stem cells in rats selectively reduces cold, but not mechanical, allodynia following L5 spinal nerve ligation ( Jwa et al, 2020 ). On the contrary, electrical stimulation of the spinal cord of SNI rats was found to reduce injury-induced mechanical allodynia without affecting cold allodynia ( Tao et al, 2021 ). Additional differences exist between rodent species.…”

NLRP3-Mediated Piezo1 Upregulation in ACC Inhibitory Parvalbumin-Expressing Interneurons Is Involved in Pain Processing after Peripheral Nerve Injury

“…Studies have shown that the expression levels of NLRP3 and IL-1β are elevated in several rodent neuropathic pain models [ 50 , 101 ]. But one team reported that SNI could not alter the expression of spinal NLRP3 inflammasome components (including IL-1β) [ 102 ], contradicting the results reported by others that SNI increased the expression of IL-1β in the serum, cerebrospinal fluid [ 103 ], and spinal cord [ 104 , 105 ]. In the present work, the administration of rrTNF to cultured BV2 cells or primary ACC neurons elevated the protein levels of Piezo1 and NLRP3 ( Figure 6 ).…”

An update on animal models of intervertebral disc degeneration and low back pain: Exploring the potential of artificial intelligence to improve research analysis and development of prospective therapeutics

“… 358 Animal models of inflammatory and neuropathic pain show inflammation regulates pain resolution by producing pro‐resolving mediators such as resolvin D1 (RvD1). 318 Resolvins are derived from, eicosapentaenonic, docosahexanoic, docosapentaenoic, and clupanodonic omega‐3 fatty acids 317 , 359 , 360 and have cell regulatory properties similar to prostaglandins promoting the restoration of normal cellular functional properties following resolution of inflammatory conditions that occur with tissue injury. Resolvins are induced in the CNS following trauma and offer exciting possibilities in the development of potential methods for the alleviation of intractable neuropathic pain in chronically affected patients.…”