Role of Specialized Pro-Resolving Mediators in Neuropathic Pain

Abstract

Inflammation and neuroinflammation are critical mechanisms in the generation of neuropathic pain that is experienced in several chronic diseases. The aberrant inflammation that triggers this pathophysiologic process can be tracked down to an exacerbated immune response, which establishes a vicious cycle and continuously recruits inflammatory cells by inducing chronic tissue damage. Recently, impairment of the cellular and molecular machinery orchestrated by specialized pro-resolving mediators (SPMs)—i.e., endogenous lipids termed resolvins, protectins, maresins, and lipoxins that confine the inflammatory cascades in space and time during the “resolution of inflammation”–has emerged as a crucial event in the derangement of the inflammatory homeostasis and the onset of chronic inflammation and pain. Indeed, a deviant inflammatory response that is not adequately controlled by the resolution network leads to the overproduction of pro-inflammatory eicosanoids that, opposite to SPMs, lead to neuropathic pain. Interestingly, in the last two decades convincing evidence has demonstrated that SPMs antagonize the in vivo activity of pro-inflammatory eicosanoids and, overall, exert potent anti-hyperalgesic effects in a number of pain-associated paradigms of disease, such as arthritis and chemotherapy-induced peripheral neuropathy, as well as in many experimental models of pain like mechanical allodynia, chemical pain, heat hypersensitivity and phase 1 and 2 inflammatory pain. Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected. Here, we aim at presenting a state-of-the-art view of SPMs, their metabolism and signalling, in the context of cellular and molecular pathways associated to neuropathic pain.

Profiling of fatty acid metabolism in the dorsal root ganglion after peripheral nerve injury

“…It is reported that 15-HEPE and 17-HDHA are precursors of lipoxin A 5 and D-series resolvins, respectively (19, ), even though we could not detect these in the present study. Lipoxins and resolvins are well-known SPM family species, and many studies have demonstrated the anti-inflammatory and analgesic properties of their pharmacological treatment (20)(21)(22)(23). The present study raises the following new questions: how are ω-3 FAs selectively subjected to LOX-mediated oxidation and why are ω-3 FA-derived metabolites transiently increased in a specified period?…”

“…These ω-3 FA-derived anti-inflammatory lipid mediators are coined "specialized pro-resolving lipid mediators" (SPMs) (19,20). Recently, there have been increasing reports regarding the pharmacological efficacy of SPMs in the treatment of pain disorders (21)(22)(23), although the biosynthetic pathways, receptors, and in vivo presence of SPMs remain to be validated (24). Whereas previous studies have reported the pathophysiological roles of specific lipid mediators of interest, comprehensive lipidomic information on pain pathology is currently lacking.…”

Lipoxins in the Nervous System: Brighter Prospects for Neuroprotection

“…Recently, roles of SPMs in neuropathic pain were elucidated, suggesting that SPM can be promising targets to counteract neuropathic pain (Leuti et al, 2021). SPM represent the endogenous inhibitors of transient receptor potential cation channel subfamily V member 1 (TRPV1), which has been with Resolvin E1 and protectin 1.…”

Creating an Optimal In Vivo Environment to Enhance Outcomes Using Cell Therapy to Repair/Regenerate Injured Tissues of the Musculoskeletal System

“…Because of its potential to also cause harm, inflammatory responses are regulated in a very complex manner, depending in part on the initiating factors, the extent of the response that is needed (i.e., the size and location of the wound) and the ability to initiate the downregulation of the response via both removal of the inciting events and elaboration of anti-inflammatory molecules, such as resolvins and related molecules [ 24 , 25 , 26 , 27 ]. In “normal” circumstances, the inflammatory response can be acute in nature followed by a resolution.…”