Pharmacological Regulation of Neuropathic Pain Driven by Inflammatory Macrophages

Abstract

Neuropathic pain can have a major effect on quality of life but current therapies are often inadequate. Growing evidence suggests that neuropathic pain induced by nerve damage is caused by chronic inflammation. Upon nerve injury, damaged cells secrete pro-inflammatory molecules that activate cells in the surrounding tissue and recruit circulating leukocytes to the site of injury. Among these, the most abundant cell type is macrophages, which produce several key molecules involved in pain enhancement, including cytokines and chemokines. Given their central role in the regulation of peripheral sensitization, macrophage-derived cytokines and chemokines could be useful targets for the development of novel therapeutics. Inhibition of key pro-inflammatory cytokines and chemokines prevents neuroinflammation and neuropathic pain; moreover, recent studies have demonstrated the effectiveness of pharmacological inhibition of inflammatory (M1) macrophages. Nicotinic acetylcholine receptor ligands and T helper type 2 cytokines that reduce M1 macrophages are able to relieve neuropathic pain. Future translational studies in non-human primates will be crucial for determining the regulatory mechanisms underlying neuroinflammation-associated neuropathic pain. In turn, this knowledge will assist in the development of novel pharmacotherapies targeting macrophage-driven neuroinflammation for the treatment of intractable neuropathic pain.

Inflammatory Macrophages in the Sciatic Nerves Facilitate Neuropathic Pain Associated with Type 2 Diabetes Mellitus

“…Thereafter, monocytes differentiate into macrophages that orchestrate inflammatory responses to repair damaged tissue and resolve the excessive inflammation (Prame Kumar et al, 2018). On the other hand, when nervous systems are damaged, cytokines, chemokines, and damage-associated molecular patterns recruit macrophages into the injured nerves, which elicit nonresolving neuroinflammation (Kiguchi et al, 2017a). Macrophages are not the only cells to accumulate in damaged nerves, as neutrophils and lymphocytes also accumulate there (Perkins and Tracey, 2000;Moalem et al, 2004;Morin et al, 2007); however, macrophages account for the largest population at the middle/late phase after nerve injury (Kiguchi et al, 2017a).…”

Tumors Provoke Inflammation and Perineural Microlesions at Adjacent Peripheral Nerves

“…Smaller lesions might occur even earlier but could not be detected due to the lack of the availability of smaller fluorescent-labelled particles. These microlesions allow the penetration of the perineurium by small molecules released by tumors (e.g., adenosine, sphingosine-1-phosphate) as well as pronociceptive and proinflammatory mediators released by macrophages and dendritic cells (e.g., prostaglandins, cytokines) [8,25] at the outside of the sciatic nerves. Whether the observed demyelination is a primary effect or whether it is a secondary effect of axonal damage due to overstimulation of the neurons remains unclear.…”

Role of Macrophage-Mediated Toll-like receptor 4–Interleukin-1R Signaling in Ectopic Tongue Pain Associated With Tooth Pulp Inflammation

“…In addition, orofacial in ammation or trigeminal nerve injury causes macrophage accumulation in the TG [6,21,26]. Accumulated macrophages release various substances, including IL-1β, that enhance neuronal excitability [4,5,7,27]. Conversely, macrophage depletion by LCCA signi cantly suppresses macrophage accumulation, which reduces TNFα release, nally resulting in the recovery of the mechanical hypersensitivity of whisker pad skin following inferior alveolar nerve transection [21].…”