In contrast to the traditional view that opioid antinociception is mediated exclusively within the central nervous system, peripheral opioid receptors have been discovered and shown to mediate analgesic effects when activated by locally applied exogenous opioid agonists. Such effects are particularly prominent in painful inflammatory conditions and have been demonstrated in both animals and humans (Barber and Gottschlich, 1992; Stein, 1995). Opioid receptors are present on peripheral sensory nerves and are up-regulated during the development of inflammation. Their endogenous ligands, opioid peptides, are expressed in resident immune cells within peripheral inflamed tissue. Environmental stimuli (stress) and releasing agents (corticotropin-releasing factor, cytokines) can liberate these opioid peptides to elicit local analgesia, and suppression of the immune system abolishes these effects. These findings have led to the concept that endogenous opioid peptides can be secreted from immunocytes, occupy opioid receptors on sensory nerves, and produce analgesia by inhibiting either the excitability of these nerves or the release of excitatory, proinflammatory neuropeptides. This chapter summarizes the discoveries that led to the formulation of this concept and discusses therapeutic implications resulting therefrom.
Peripheral Analgesic Effects of Exogenous Opioids
The basis for the concept just described has emerged from animal experiments investigating local analgesic actions of opioids in peripheral tissues. Interestingly, almost all of these studies have used models of inflammation. In those models exogenous opioid agonists produce potent local antinociception. Different strategies have been used to exclude central effects – for example, compounds that do not cross the blood-brain barrier (Chang et al., 1996) or the local versus systemic application of equivalent doses of agents (Stein, 1993; Stein et al., 1997).
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