- Email: [email protected]
Genetics in pain management
Acta Anaesthesiologica Taiwanica 49 (2011) 1–2
Contents lists available at ScienceDirect
Acta Anaesthesiologica Taiwanica journal homepage: www.e-aat.com
Editorial View
Genetics in pain management
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 1973,1–3 the molecular cloning of opioid receptors since 1992,4–8 and the extensive splicing studies starting 1995.9–12 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 splicing9–12) 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,19–22 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. References 1. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973;179:1011–4. 2. Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic [3H]etorphine to rat-brain homogenate. Proc Natl Acad Sci USA 1973;70:1947–9. 3. Terenius L. Characteristics of the “receptor” for narcotic analgesics in synaptic plasma membrane from rat brain. Acta Pharmacol Toxicol 1973;33: 377–84. 4. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG. The d-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA 1992;89:12048–52. 5. Evans CJ, Keith Jr DE, Morrison H, Magendzo K, Edwards RH. Cloning of a delta opioid receptor by functional expression. Science 1992;258:1952–5. 6. Thompson RC, Mansour A, Akil H, Watson SJ. Cloning and pharmacological characterization of a rat m opioid receptor. Neuron 1993;11:903–13.
1875-4597/$ – see front matter Copyright Ó 2011, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.aat.2011.03.001
2 7. Wang JB, Imai Y, Eppler CM, Gregor P, Spivak CE, Uhl GR. m opiate receptor: cDNA cloning and expression. Proc Natl Acad Sci USA 1993;90: 10230–4. 8. Li S, Zhu J, Chen C, Chen YW, Deriel JK, Ashby B, et al. Molecular cloning and expression of a rat kappa opioid receptor. Biochem J 1993;295:629–33. 9. Rossi GC, Pan YX, Brown GP, Pasternak GW. Antisense mapping the MOR-1 opioid receptor: evidence for alternative splicing and a novel morphine-6bglucuronide receptor. FEBS Lett 1995;369:192–6. 10. Schuller AG, King MA, Zhang J, Bolan E, Pan YX, Morgan DJ, et al. Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1. Nat Neurosci 1999;2:151–6. 11. Pan L, Xu J, Yu R, Xu MM, Pan YX, Pasternak GW. Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm. Neuroscience 2005;133:209–20. 12. Pan YX, Xu J, Xu M, Rossi GC, Matulonis JE, Pasternak GW. Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions. Proc Natl Acad Sci USA 2009;106:4917–22. 13. Pasternak G, Pan YX. Mu opioid receptors in pain management. Acta Anaesthesiol Taiwan 2011;49:21–5. 14. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, et al. Single nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci 1998;95:9608–13. 15. Zuo Z. The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance. Anesth Analg 2005;101:728–34.
Editorial View 16. Labroo RB, Paine MF, Thummel KE, Kharasch ED. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy and drug interactions. Drug Metab Dispos 1997;25:1072–80. 17. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2005;352:638. 18. Sweeney BP. Pharmacogenomics and anesthesia: explaining the variability in response to opiates. Eur J Anesth 2007;24:209–12. 19. Chien CC, Pasternak GW. Functional antagonism of morphine analgesia by (þ)-pentazocine: evidence for an anti-opioid sigma 1 system. Eur J Pharmacol 1993;250:R7–8. 20. Chien CC, Pasternak GW. Selective antagonism of opioid analgesia by a sigma system. J Pharmacol Exp Ther 1994;271:1583–90. 21. Chien CC, Carroll FI, Brown GP, Pan YX, Bowen W, Pasternak GW. Synthesis and characterization of [125I]3’-()-iodopentazocine, a selective sigma 1 receptor ligand. Eur J Pharmacol 1997;321:361–8. 22. Kim FJ, Kovalshyn I, Burgman M, Neilan C, Chien CC, Pasternak GW. s1 receptos modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding. Mol Pharmacol 2010;77:695–703.
Chih-Cheng Chien Sijhih Cathay General Hospital, Taiwan E-mail: [email protected]
Contents lists available at ScienceDirect
Acta Anaesthesiologica Taiwanica journal homepage: www.e-aat.com
Editorial View
Genetics in pain management
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 1973,1–3 the molecular cloning of opioid receptors since 1992,4–8 and the extensive splicing studies starting 1995.9–12 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 splicing9–12) 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,19–22 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. References 1. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973;179:1011–4. 2. Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic [3H]etorphine to rat-brain homogenate. Proc Natl Acad Sci USA 1973;70:1947–9. 3. Terenius L. Characteristics of the “receptor” for narcotic analgesics in synaptic plasma membrane from rat brain. Acta Pharmacol Toxicol 1973;33: 377–84. 4. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG. The d-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA 1992;89:12048–52. 5. Evans CJ, Keith Jr DE, Morrison H, Magendzo K, Edwards RH. Cloning of a delta opioid receptor by functional expression. Science 1992;258:1952–5. 6. Thompson RC, Mansour A, Akil H, Watson SJ. Cloning and pharmacological characterization of a rat m opioid receptor. Neuron 1993;11:903–13.
1875-4597/$ – see front matter Copyright Ó 2011, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.aat.2011.03.001
2 7. Wang JB, Imai Y, Eppler CM, Gregor P, Spivak CE, Uhl GR. m opiate receptor: cDNA cloning and expression. Proc Natl Acad Sci USA 1993;90: 10230–4. 8. Li S, Zhu J, Chen C, Chen YW, Deriel JK, Ashby B, et al. Molecular cloning and expression of a rat kappa opioid receptor. Biochem J 1993;295:629–33. 9. Rossi GC, Pan YX, Brown GP, Pasternak GW. Antisense mapping the MOR-1 opioid receptor: evidence for alternative splicing and a novel morphine-6bglucuronide receptor. FEBS Lett 1995;369:192–6. 10. Schuller AG, King MA, Zhang J, Bolan E, Pan YX, Morgan DJ, et al. Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1. Nat Neurosci 1999;2:151–6. 11. Pan L, Xu J, Yu R, Xu MM, Pan YX, Pasternak GW. Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm. Neuroscience 2005;133:209–20. 12. Pan YX, Xu J, Xu M, Rossi GC, Matulonis JE, Pasternak GW. Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions. Proc Natl Acad Sci USA 2009;106:4917–22. 13. Pasternak G, Pan YX. Mu opioid receptors in pain management. Acta Anaesthesiol Taiwan 2011;49:21–5. 14. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, et al. Single nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci 1998;95:9608–13. 15. Zuo Z. The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance. Anesth Analg 2005;101:728–34.
Editorial View 16. Labroo RB, Paine MF, Thummel KE, Kharasch ED. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy and drug interactions. Drug Metab Dispos 1997;25:1072–80. 17. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2005;352:638. 18. Sweeney BP. Pharmacogenomics and anesthesia: explaining the variability in response to opiates. Eur J Anesth 2007;24:209–12. 19. Chien CC, Pasternak GW. Functional antagonism of morphine analgesia by (þ)-pentazocine: evidence for an anti-opioid sigma 1 system. Eur J Pharmacol 1993;250:R7–8. 20. Chien CC, Pasternak GW. Selective antagonism of opioid analgesia by a sigma system. J Pharmacol Exp Ther 1994;271:1583–90. 21. Chien CC, Carroll FI, Brown GP, Pan YX, Bowen W, Pasternak GW. Synthesis and characterization of [125I]3’-()-iodopentazocine, a selective sigma 1 receptor ligand. Eur J Pharmacol 1997;321:361–8. 22. Kim FJ, Kovalshyn I, Burgman M, Neilan C, Chien CC, Pasternak GW. s1 receptos modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding. Mol Pharmacol 2010;77:695–703.
Chih-Cheng Chien Sijhih Cathay General Hospital, Taiwan E-mail: [email protected]