OPIOIDS AND PAIN

1. The central nervous system:in mammals is able to react to painful s timuli at many levels that are involved in transmission, modulation an d sensation of pain. Endogenous opioid peptides and their receptors ar e located at key points in pain pathways, and response to pain can be modulated by local application of opioids at many sites. Mechanisms of opioid analgesia at peripheral, spinal, medullary and midbrain levels are only incompletely understood; forebrain systems are even less app reciated. Local circuits in the spinal dorsal horn play a critical rol e in processing nociceptive afferent input and in mediating the action s of descending pain modulating systems. 2. The opioid receptors, rece ntly cloned, exert their effects by activating G protein coupled effec tor systems, such as ion channels and second messenger systems. Althou gh the receptor most commonly associated with pain relief is the mu-re ceptor, specific delta- and kappa-agonists can also mediate antinocice ption at spinal and supraspinal sites. Acute effects of opioids on tar get neurons are inhibitory, but excitatory effects have also been repo rted. 3. Noxious stimulation increases neuronal activity and modulates expression of genes, including immediate-early genes and neuropeptide (i.e. opioid) genes at spinal and supraspinal levels of the somatosen sory system. Opioid drugs and endogenously released opioid peptides ca n modulate signal transduction mechanisms and intracellular processes that lead to alterations in protein phosphorylation and gene expressio n. These effects of opioids at the cellular level may underlie the mec hanisms of pre-emptive analgesia and neuroplastic changes such as tole rance, dependence, sensitization, hyperalgesia, adaptation, addiction, and modulation of pain memories.