Opioids: the good, the bad? and the future (Proceedings)
Synthetic opioids are powerful, useful tools to manage pain for one simple reason: Receptors for naturally-occurring opioids (endorphins, enkephalins) are distributed ubiquitously throughout the body and can be found in both central and peripheral tissues. Several opioid different receptor types and subtypes have been isolated, each with a variant effect. The historic categorization of mu, kappa, delta, and sigma opioid receptor subtypes have been re-classed according to a rubric aligned with gene expression. However for the sake of our discussions, this manuscript to familiar and traditional Greek-letter categories, and in particular mu and kappa receptors as these are the two that are manipulated in animals to provide analgesia.
Activation of a mu-opioid receptor inhibits presynaptic release (especially in the dorsal horn of the spinal cord) and postsynaptic response (especially in the dorsal root ganglion) to excitatory neurotransmitters. The proposed mechanism includes opioid receptor coupling with the membrane-associated G protein; this leads to decreased intracellular formation of cAMP which diminishes calcium channel phosphorylation (closing off the voltage-gated calcium channel) and opens potassium channels enhancing potassium influx. The resulting effect is hyperpolarization of the neuron and blockade of Substance P release. Nociceptive transmission is thus greatly impeded.
Opioid tolerance and resistance occurs when signaling cascades force calcium channels to remain open despite the presence of opioid. Additionally, glial cells, once thought to merely provide supporting roles in the spinal cord but are now known to be highly interactive with nociceptors, dysregulate opioids...and unfortunately, opioids activate glial cells. Therefore in an important sense, the pain we perceive is a balancing act between the activity of the opioids and the activity of glia.A number of different opioid drugs are available which vary in their relative potency and receptor affinity.