PERIPHERAL MECHANISMS OF OPIOID ANALGESIA

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In experimental and controlled clinical studies peripherally acting opioids have been shown to effectively relieve inflammatory pain. In addition to locally applied exogenous opioids, the release of endogenous opioid peptides from immune cells of inflamed tissue by agents such as corticotropin releasing factor (CRF) and interleukin-1 (IL-1) produces potent analgesia. Such peripheral effects are of considerable interest in view of the avoidance of centrally mediated side effects of opioid analgesics, such as dysphoria, dependence, addiction, sedation and respiratory depression. In our most recent research we investigated two new aspects of peripheral opioid analgesia: i) the influence of the inflammatory process on the analgesic efficacy of opioids and on the effective number and mRNA of mu-opioid receptors in primary sensory neurons; ii) the anatomical localization and characteristics of CRF and IL-1beta receptors in rats with unilateral painful inflammation of the hindpaw. In our first study we found that inflammation initiates an early onset and subsequent increase in peripheral mu-opioid receptor-mediated analgesic effects of DAMGO. Basal levels of mu-opioid receptor mRNA are abundant in dorsal root ganglia of naive animals and suggest that mu-opioid receptors are preexistent on peripheral sensory nerve terminals. These levels do not change during the early period (up to 24 h) of inflammation. At later stages, however, the number of peripheral mu-opioid receptors increases, whereas mu-opioid receptor mRNA remains unchanged. Thus, an up-regulation in the number of peripheral mu-opioid receptors may not account for the enhanced analgesic effects of opioids at early, but at later stages of inflammation. The second study demonstrated that four days after i.pl. injection of Freund's adjuvant, 125I-CRF and 125I-IL-1beta binding sites are found on immune cells in lymph nodes (LN) and inflamed paws. This binding is of high affinity and displaceable by the respective unlabeled agonist and antagonist ligands, but not by opioid or adrenergic compounds. These binding sites are practically absent on nerves and in noninflamed subcutaneous tissue but their number is greatly enhanced in inflamed paws and LN. In context with our previous studies, this upregulation of binding sites for the opioid releasing agents CRF and IL-1beta represents part of the body's local response to combat inflammatory pain.