Attacking Pain At Its Source: New Perspectives on Opioids

Christoph Stein, Michael Schäfer, Halina Machelska


Nat Med. 2003;9(8) 

In This Article

Peripheral and central opioid receptors

Three cDNAs and their genes have been identified, encoding the µ-, - and -opioid receptors (MOR, DOR and KOR, respectively)[1]. All three receptors mediate pain inhibition and are found throughout the nervous system, in somatic and visceral sensory neurons, spinal cord projection and interneurons, midbrain and cortex. The locations of different opioid receptors on functionally distinct cell types within local circuits of the brain and spinal cord can result in additive or sometimes opposing interactions between receptor types (for example, KOR can have antianalgesic actions)[1,4].

Recently, opioid receptors have been identified on peripheral processes of sensory neurons (Fig. 1). The cell bodies of these neurons in dorsal root ganglia express all three mRNAs and receptor proteins (reviewed in ref. 5). Opioid receptors are intra-axonally transported into the neuronal processes[6,7,8,9,10] and are detectable on peripheral sensory nerve terminals in animals[9,11,12,13] and humans[14]. Colocalization studies confirmed the presence of opioid receptors on C- and A-fibers[15], on vanniloid receptor-1-positive visceral fibers[16] and on neurons expressing isolectin B4, substance P or calcitonin gene-related peptide[13,17,18], consistent with the nociceptor phenotype. Sympathetic neurons and immune cells can also express opioid receptors but their functional role is unclear[8,19,20]. The binding characteristics of peripheral and central opioid receptors are similar[8,21] but the molecular mass of peripheral and central MORs seems to be different[9]. If these findings are confirmed, a search for selective ligands at such distinct receptors may be warranted.

Figure 1.

Opioid receptor transport and signaling in primary afferent neurons. Opioid receptors and neuropeptides (such as substance P) are synthesized in the dorsal root ganglion and transported along intra-axonal microtubules into central and peripheral processes of the primary afferent neuron. At the terminals, opioid receptors are incorporated into the neuronal membrane and become functional receptors. Upon activation by exogenous or endogenous opioids, opioid receptors couple to inhibitory G-proteins. This leads to direct or indirect (through decrease of cyclic adenosine monophosphate) suppression (-) of Ca2+ or Na+ currents, and subsequent attenuation of substance P release. The permeability of the perineurium is increased within inflamed tissue. OR, opioid receptor; sP, substance P; EO, exogenous opioids; OP, endogenous opioid peptides; Gi/o, inhibitory G proteins; cAMP, cyclic adenosine monophosphate.

There is no dispute that peripheral, spinal and supraspinal opioid receptors mediate analgesic effects. However, the relative contribution of each site to a given analgesic effect after the systemic (intravenous or oral) administration of an opioid agonist has not been examined thoroughly. Recent studies suggest that systemically[22,23] and even centrally (intracerebroventricularly) injected opioid agonists may act predominantly through peripheral opioid receptors. This finding was attributed to the active transport of opioids from the brain to the blood by the saturable P-glycoprotein pump within endothelial cells of the blood-brain-barrier[24]. Finally, tissue damage stimulates the expression of peripheral opioid receptors, which likely leads to a concomitant increase of their function.


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