In the postgenome era, with the help of high-throughput research tools, our knowledge about genetic and molecular mechanisms responsible for nociception and pain accumulates in a much faster way than before. Interestingly, based on these newly derived data, the old drug for pain control, the opiates, and their responding receptors, the opioid receptors, remain to be the most promising solution for pain relief. However, although opioids are powerful in treating pain, their diverse pharmacological effects between patients remain a challenge for clinicians. Clinicians often find that while a certain dose of opioid is adequate to relief pain in one patient, a dose up to 10-fold or even more may be required in another patient to achieve acceptable pain scores. The same occurs in the development of side effects. While some patients are vulnerable to nausea or constipation, others are not. Many scientists therefore devote themselves to the exploration of the complicated mechanisms behind opioid analgesia. Among all their scientific outputs, three categories of research are thought to be major milestones. They are, according to the time sequence, the biochemical identification of opioid receptors in 1973,1, 2, 3 the molecular cloning of opioid receptors since 1992,4, 5, 6, 7, 8 and the extensive splicing studies starting 1995.9, 10, 11, 12 These studies together provide a fundamental picture for most phenomena related to the clinical usage of opioids in pain management. To provide the readers of Acta Anaesthesiologica Taiwanica a decent review about these major events, we are honored to be able to invite Professor Gavril Pasternak, who has long been recognized as a major contributor and leading scholar in the study of opioids and opioid receptors, and is currently the Anne Burnett Tandy Chair in Neurology and head of the Laboratory of Molecular Neuropharmacology at Memorial Sloan-Kettering Cancer Center, to present an outstanding article13 addressing all these intriguing findings about mu opioid receptors. We believe that our readers may benefit a lot from this wonderful review.
In addition to the diverse genetic coding of opioid receptors, which has already been illustrated in the review, there are still other genetic variations contributing to the even more diverse clinical phenotypes. Considering direct pharmacological effect elicited by opioid receptors, both kinetic and dynamic factors could be different genetically. For example, mutation14 or polymorphism (such as splicing9, 10, 11, 12) of opioid receptors and their associated phosphorylation regulators15 may certainly be responsible for many dynamic variants. As for kinetic factors, mutations affecting cytochrome P450 enzymes (CYP) involved in the metabolism of opioid prodrugs, such as CYP3A416 and CYP2D6,17 are demonstrated to affect both therapeutic and side effects of some opioids, such as codeine and tramadol. Other genetic differences affecting the absorption, protein binding, and transmembrane transportation of opioids may also change the kinetic properties of opioids significantly.18 In the presence of all these possible genetic variations, no wonder patients respond to opioids quite differently.
There are at least two more categories of genetic factors contributing to the diverse response in using opioid for pain management. One is those determining the sensitivity to nociceptive stimuli, while the other is those modulating opioid analgesia in neuronal circuit. For the first one, genes involved in the firing of peripheral nociceptors, the conduction of nerve impulses, the efficacy of synaptic transmission, the generation of excitatory or inhibitory postsynaptic potentials, the development of neuronal plasticity, and the functioning of pain-sensation related central nervous systems are all possible candidates. For the second, genes responsible for neuronal transmitters or pathways modulating analgesia centrally, such as monoamines18 and sigma1 receptor,19, 20, 21, 22 should be considered.
What will be coming for clinical application with all these knowledge integrated in the future? People are expecting that with all the pharmacogenetic information collected, personal genetic profiling databank will be established with the help of currently available gene chips or other high-throughput screening devices. The pharmacologic effect of drugs used may therefore be more predictable. Before that, a simple chip consisting a collection of genes controlling specific phenotypes for a certain drug, such as opioid, may be available for more precise delivery of these potentially hazardous drugs. No matter what, the contribution made by genetic researches is certainly enormous to future health care industry, including the management of pain.