Interleukin-1 -and corticotropin releasing factor-induced release of β-endorphin from immune cells and inhibition of inflammatory pain

Abstract

Local analgesic effects of exogenous opioid agonists are particularly prominent in painful inflammatory conditions and are mediated by opioid receptors on peripheral sensory nerves (1–3). The endogenous ligands of these receptors, opioid peptides, have been demonstrated in resident immune cells within inflamed tissue of animals and humans (4–6). This study demonstrates in vitro that interleukin-1 (IL-1) and corticotropin releasing factor (CRF) produce acute release of immunoreactive β-endorphin in cell suspensions freshly prepared from inflamed lymph nodes (7). This effect was reversible by IL-1 receptor antagonist or α-helical CRF, respectivly. In in vivo experiments local, but not systemic application of IL-1 and CRF resulted in potent analgesia in inflamed paws. This effect was reversed by IL-1 receptor antagonist (IL-1 ra) or α-helical CRF, respectively, and by cyclosporine A. In vivo administration of antibodies against opioid peptides indicates that the effects of IL-1 and CRF are mediated by β-endorphin and, in addition, by dynorphin A and [Met]enkephalin, respectively. Correspondingly, IL-1 effects are inhibited by μ-, ∂- and κ- opioid antagonists, whereas CRF effects are attenuated by all except a κ- antagonist (7). In conclusion, both IL-1 and CRF activate their receptors on immune cells to release opioids (predominantly β-endorphin) that subsequently occupy their corresponding receptors on sensory nerves and result in antinociception.