Targeting novel peripheral mediators for the treatment of chronic pain

Abstract

Research efforts over the past two decades have helped us better understand the biological mechanisms that lead to chronic pain. Despite this, there has been limited progress in developing novel analgesics to treat sufferers of persistent pain conditions, who may account for as many as one-fifth of the population. A re-evaluation of the strategies used to discover pain-relieving drugs is needed to meet this widespread clinical need. Here, we discuss the merits of pursuing peripherally acting pain mediators. We review the significant clinical evidence that neuronal activity from the periphery is a major contributor to painful symptom production and that peripheral mediators play a substantial role in this aberrant nociceptor activity. We discuss the clinical benefits of blocking individual known mediators and describe our own approach to identify novel mediators.

Standardized Profiling of The Membrane-Enriched Proteome of Mouse Dorsal Root Ganglia (DRG) Provides Novel Insights Into Chronic Pain

“…We focused our analysis on DRG isolated from male mice subjected to two different chronic pain states. As DRG harbor primary sensory neurons, which are the interface of the nervous system with external and internal environments, they are crucially implicated in the beginning of somatosensory pathways including nociception (3,4,86). This, together with their accessibility, renders DRG key cellular targets for analgesic therapies (2,4,87).…”

The Dorsal Root Ganglion as a Therapeutic Target for Chronic Pain

“…Their inward currents increase nociceptive communication (1). Calcium currents can be reduced via medications that directly target specific subunits of the channel protein structure; gabapentin and ziconotide are 2 examples of antagonists that are effective pain medications (2). Calcium channel currents can also be inhibited via indirect means; application of neuraminidase inhibits the glycosylation that is necessary for normal channel function (3) and TAT-CBD3 blocks the function of CRMP2 (4).…”

“…B, Vanilloid receptors including TRPV1 are up-regulated in pain conditions, influenced by the function of its regulator peptide AT2R, and their cationic currents are algogenic (1). Prolonged application of agonists such as capsaicin and resiniferatoxin paradoxically desensitize TRPV1 channels and reduce cationic currents (2), similar to the action of antagonists such as AZD1386 (3). Additionally, antagonism of AT2R with EMA300 reduces TRPV1 currents (4).…”

A Review of Intravenous Lidocaine Infusion Therapy for Paediatric Acute and Chronic Pain Management

“…On-going input from peripheral nociceptors which is blocked by local anaesthetics is used to explain dependence of pain syndromes on peripheral inputs [175]. However, IVLT also has a central effect reducing components of pain caused by central nervous system injuries [176].…”

“…However, prolonged relief has been reported in animal models [274] and in some non-randomized [255,275] and randomized trials [175,276,277]. The Canadian Pain Society states that "intravenous lidocaine infusions are generally safe and can provide significant pain relief for 2-3 weeks at a time" [278].…”