Modulating Pain in the Periphery

Abstract

This article provides a brief overview of earlier work of our group on the peripheral signaling of pain, summarizes more recent studies on the role of opioids in chronic neuropathic pain, and speculates on the future of gene-based therapies as novel strategies to enhance the peripheral modulation of pain. Neurophysiological and psychophysical studies have revealed features of primary afferent activity from somatic tissue that led to improved understanding of the physiology and pathophysiology of pain signaling by nociceptive and non-nociceptive fibers. The demonstration of peripheral opioid mechanisms in neuropathic pain suggests a potential role for these receptors in the modulation of pain at its initiation site. Our work has focused on characterizing this peripheral opioid analgesia in chronic neuropathic pain such that it can be exploited to develop novel and potent peripheral analgesics for its treatment. Ongoing research on virus-mediated gene transfer strategies to enhance peripheral opioid analgesia is presented.

Opioid Receptors

“…Current research pursues the development of systemically applicable opioid agonists and enkephalinase inhibitors that do not permeate the blood-brain, intestinal, or placental barriers (4,63,68,69,101,104,105). In addition, gene-therapeutic approaches enhancing the expression of peripheral opioid receptors and peptides are being investigated (106,107). Thus, the selective activation of peripheral opioid receptors promises advantages such as antiinflammatory actions and the absence of side effects typical for conventional opioids (sedation, nausea, apnea, fetal/neonatal depression, addiction) or nonsteroidal analgesics (gastrointestinal ulcers, bleeding, stroke, myocardial infarction) (91,108).…”

Targeting pain and inflammation by peripherally acting opioids

“…Thus, the development of inflammatory and neuropathic pain is counteracted by immune cells producing and secreting opioid peptides. Gene therapeutic approaches are aiming to increase the production of opioid peptides and receptors in inflammatory cells and peripheral sensory neurons, respectively (Stein and Machelska, 2011; Raja, 2012). Preventing the extracellular degradation of endogenous opioid peptides by peptidase inhibitors as well as nanocarrier-directed transport of opioids have been shown to diminish inflammatory pain (Roques et al, 2012; Schreiter et al, 2012; Hua and Cabot, 2013).…”