Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control

Abstract

Opioid receptors are widely expressed in the central and peripheral nervous system as well as in numerous nonneuronal tissues. Both animal models and human clinical data support the involvement of peripheral opioid receptors in analgesia, particularly in inflammation where both opioid receptor expression and efficacy are increased. Immune cells have been shown to contain numerous opioid peptides such as beta-endorphin (END), met-enkephalin (ENK), and dynorphin-A (DYN), although the predominant opioid peptide involved in immune-cell mediated antinociception is thought to be END. These opioid-containing immune cells migrate to inflamed tissues during a complex process of recruitment by chemokines, adhesion, and extravasation. In these tissues, opioid peptide is released from the immune cells upon stimulation with corticotrophin-releasing factor (CRF), noradrenaline, and interleukin 1beta (IL-1beta), and the immune cells return to the local lymph node depleted of peptide. Consistent with this model, systemic immunosuppression may lead to impaired endogenous analgesia as competent immune cells are essential to achieve release of endogenous opioid peptides within inflamed tissue. A further level of complexity is added by the observation that exogenous opioids may impair immune cell function, although there is some evidence to suggest that endogenous opioid peptides do not share this immunosuppressive effect. Improving our understanding of endogenous opioid mechanisms will provide valuable insight towards the development of novel treatments for pain with improved side effect profiles.

Figure 1

Proposed model for opioid receptor-mediated analgesia at peripheral terminals of primary sensory neurons. Activation of opioid receptors by endogenous or exogenous opioid agonists promotes G-protein coupling. Opioid receptor-coupled G-proteins directly activate inwardly rectifying K⁺ channels (GIRK⁺), inhibit voltage-dependent Ca²⁺ channels, and inhibit adenylyl cyclase (AC). Opioid receptors indirectly activate phospholipase C (PLC), the mitogen-activated protein kinase (MAPK) cascade, and large conductance Ca²⁺-activated K⁺ channels by utilizing other intermediary messenger systems.

Figure 2

Endogenous opioid peptides are released by immune cells to reduce inflammatory pain. Adhesion molecules expressed on immune cells and inflamed endothelium coordinate the migration of circulation immune cells into inflamed tissue. The proinflammatory mediators corticotropin-releasing factor (CRF) and interleukin-1β (IL-1β), as well as the sympathetic neurotransmitter, noradrenaline, stimulate immune cells to secrete their opioid peptides. These peptides activate opioid receptors located on the peripheral ends of sensory neurons and effectively reduce inflammatory pain. Immune cells, devoid of their opioid contents, then continue their passage to neighbouring lymph nodes.