Peripherally-Acting Opioids

Opioids are broad-spectrum analgesics with potent pain-relieving qualities but alsowith potential adverse effects related to both short-term and long-term therapy. Researchers have attempted to alter existing opioid analgesics, utilize different routes/formulations, or combine opioid analgesics with other compounds in efforts to improve analgesia while minimizing adverse effects. Exogenous opioids, administeredin efforts to achieve analgesia, work by mimicking the actions of endogenous opioids. Endogenous opioids and their receptors are located in the brain (supraspinal areas), spinal cord, and periphery. Although opioids and opioid receptors in thebrain and spinal cord have received much attention over many years, peripheral endogenous opioid analgesic systems have only been extensively studied during thepast decade. It has been known since 1990 that following injection into the rodenthindpaw, d-Ala2, N-Me-Phe4, Gly5-ol-enkephalin (DAMGO) [a muopioid receptor agonist] probably exerts its antinociceptive effects locally, since the doses administeredare too low to have an effect in the central nervous system (CNS). This notion hasbeen supported by the observation that the quaternary compound morphine methyliodide, which does not as readily cross the bloodbrain barrier and enter the CNS,produced antinociception following intradermal administration into the hindpaw,but not when the same dose was administered systemically (subcutaneously at adistant site). With a growing appreciation of peripheral endogenous opioids, peripheral endogenous opioid receptors, and peripheral endogenous opioid analgesicsystems, investigators began growing hopeful that it may be possible to achieve adequate analgesics while avoiding unwanted central untoward adverse effects (e.g.respiratory depression, somnolence, addiction). Peripherally-acting opioids, whichcapitalize on peripheral endogenous opioid analgesic systems, may be one potential future strategy which may be utilized in efforts to achieve potent analgesia withminimal side effects.Key words: Pain, opioids, immune cells, peripherally-acting opioids (PAO), leukocytes, inflammatory pain, peripheral analgesia