Leukocyte-Derived Opioid Peptides and Inhibition of Pain

Abstract

In peripheral inflamed tissue interactions between leukocyte-derived opioid peptides and opioid receptors on sensory neurons lead to potent, clinically relevant inhibition of pain. 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, which migrate to injured tissues directed by chemokines and adhesion molecules. Under stressful stimuli or in response to releasing agents (e.g., corticotropin-releasing factor, cytokines, catecholamines) leukocytes can secrete opioids. These peptides activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. These effects occur without central opioid side effects such as depression of breathing, clouding of consciousness, or addiction. Future research should elucidate the selective targeting of opioid peptide-containing immune cells to sites of painful tissue injury and the augmentation of opioid peptide and receptor synthesis.

The Novel Roles of Neutrophils Via Opioid Peptides: Regulation of the Estrous Cycle and Pain

“…C. Stein and H. Machelska (2006). They obtained several lines of evidence supporting such a regulatory mechanism, as follows.…”

“…(5) Administration of CRH to the site of inflammation decreases pain, whereas neutralization of CRH at the site of inflammation increases pain (Labuz et al 2009;Machelska and Stein 2006;Rittner et al 2006). (6) In CRH-or IL-1b-induced pain inhibition, leukocytes apparently are the target, because depletion of granulocytes as well as blockade of chemokines (MIP-2 and KC) results in a significant reduction in opioid-containing cells and pain inhibition (Machelska and Stein 2006). (2) and (4) also support the neutrophil-dependent regulatory mechanism by which the estrous cycle is maintained.…”

“…If the possibility is proven correct, then there is the possibility that IL-1 in neutrophils may also participate in regulation of the estrous cycle. Since IL-1 causes opioid peptide release (Machelska and Stein 2006), IL-1 may regulate the estrous cycle via opioid peptides.…”

“…Although IL-1, CRH and IL-8 appear to be involved in regulation of pain by neutrophils (Machelska and Stein 2006), IL-1 (Takacs et al 1988), CRH (Xu et al 2007) and MIP-2 (Sasaki et al 2009) are also detected in the ovary even under physiological conditions. Consequently, it is possible that these molecules are responsible for opioid peptide release from neutrophils in both processes, and the difference between these two processes may be quantitative but not qualitative.…”

“…Because neutrophils are reported to regulate pain through opioid peptides such as b-endorphin at inflammatory sites (Machelska and Stein 2006), I would like to summarize our results and compare these two phenomena in this review.…”