Immune mechanisms in pain control.

Classically, pain sensation or suppression has been attributed exclusively to neuronal circuits. This review challenges this notion and presents an expanded concept about the contribution of immune mechanisms in the inhibition of pain (analgesia). Among the many transmitters with potential for neuroimmune interactions, we concentrate here on opioids, the most extensively investigated compounds. Pain inhibition mediated by immune-derived opioids results from interactions with the peripheral nervous system. A prerequisite for the manifestation of such effects seems to be inflammation, accompanied by hyperalgesia. Opioid receptors are present on peripheral terminals of sensory neurons and are upregulated in inflammation. Their endogenous ligands, opioid peptides, are synthesized in circulating immune cells that under pathological conditions migrate to injured tissue. This is orchestrated by selectins and other adhesion molecules located on opioid-containing immune cells and on vascular endothelium. Under stressful stimuli or in response to releasing agents (e.g., corticotropin-releasing hormone or cytokines), immunocytes can secrete opioids. These peptides activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves, the release of excitatory neuropeptides, or both. Because these effects occur in the periphery, they are devoid of central opioid side effects, such as respiratory depression, sedation, dysphoria, or dependence. Targeting of immune cells containing opioids to injured tissues is a novel concept of pain control and opens potential new therapeutic approaches.