Neuroimmune Interaction in the Regulation of Peripheral Opioid-Mediated Analgesia in Inflammation

Abstract

Peripheral immune cell-mediated analgesia in inflammation is an important endogenous mechanism of pain control. Opioid receptors localized on peripheral sensory nerve terminals are activated by endogenous opioid peptides released from immune cells to produce significant analgesia. Following transendothelial migration of opioid-containing leukocytes into peripheral sites of inflammation, opioid peptides are released into a harsh milieu associated with an increase in temperature, low pH, and high proteolytic activity. Together, this microenvironment has been suggested to increase the activity of opioid peptide metabolism. Therefore, the proximity of immune cells and nerve fibers may be essential to produce adequate analgesic effects. Close associations between opioid-containing immune cells and peripheral nerve terminals have been observed. However, it is not yet determined whether these immune cells actually form synaptic-like contacts with peripheral sensory terminals and/or whether they secrete opioids in a paracrine manner. This review will provide novel insight into the peripheral mechanisms of immune-derived analgesia in inflammation, in particular, the importance of direct interactions between immune cells and the peripheral nervous system.

Keywords: immune cells; inflammation; neuroimmune; opioids; pain; peripheral nervous system.

Figure 1

Migration of opioid-containing immune cells and opioid release within inflamed tissue. Adhesion molecules interact with their respective ligands to facilitate endothelial transmigration of immune cells. In response to stress or releasing agents (e.g., CRF, IL-1, and CXCL8), the immune cells secrete opioid peptides. Opioid peptides or exogenous opioids bind to opioid receptors on primary afferent neurons, leading to analgesia. The immune cells, depleted of opioids, then migrate to regional lymph nodes. The arrows denote an increased expression within inflamed tissue of cell adhesion molecules, opioid receptors, endogenous opioid peptides, and receptors for ligands that trigger opioid release on the surface of immune cells (e.g., CXCR2, IL-1 receptors, and CRF receptors). All these enhance the analgesic activity of the peripheral opioid pathway in inflammatory conditions. Figure adapted from Ref. (2).

Figure 2

The inflammatory milieu is associated with an increase in temperature, low pH, and high proteolytic activity, which together has been suggested to increase the degradation of opioid peptides (1, 23). Therefore, direct adhesion between opioid-containing immune cells and peripheral sensory neurons, via adhesion molecules (e.g., ICAM-1 and/or NCAM), may be necessary to release opioid peptides within the effective range of peripheral opioid receptors to produce adequate analgesia. On activation by opioid agonists, opioid receptors undergo conformational changes allowing intracellular coupling of inhibitory G proteins to the C terminus of opioid receptors. This leads to inhibition of calcium and/or sodium channels and a decrease in the level of neuronal cAMP. In addition, opioids reduce the excitability of nociceptors, the propagation of action potentials, and the release of excitatory and/or pro-inflammatory factors (e.g., substance P, TNF-α, and NA) from peripheral sensory neurons.