Molecular and Biochemical Mechanisms of Analgesic Response to Morphine and Other Opioids - Coursework Example

Molecular and Biochemical Mechanisms of Analgesic Response to Morphine and Other Opioids Morphine, discovered by Freidrich Serturner, a German pharmacist, in 1806, has been used clinically ever since to alleviate severe pain. Chemically, the alkaloid is (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol (Figure 1). Morphine, its derivatives including codeine (methylmorphine, Fig.2) and heroin (diacetylmorphine, Fig.3), and opioids such as fentanyl (N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide, Fig.4), levorphanol (levo-3-hydroxy-N-methylmorphinan, Fig.5) and methadone (6-dimethylamino-4,4-diphenyl-3-heptanone, Fig.6) have become some of the most widely used drugs for treatment of acute pain but a serious disadvantage is their addiction liability. Fig. 1. Morphine Fig. 2. Codeine Fig. 3. Heroin Fig. 4. Fentanyl Fig. 5. Levorphanol Fig. 6. Methadone (Source for Figs. 1-6: http://www.opioids.com/chemical/index.html) Metabolites of morphine Morphine is the ideal opioid analgesic. The most important positions on the morphine molecule, in terms of their implications for activity as well as metabolism, are the phenolic hydroxyl at position 3, the alcoholic hydroxyl at position 6, and at the nitrogen atom (Figure 1). Conjugation with glucuronic acid is an important metabolic pathway for the inactivation and elimination of several compounds especially drugs, dietary chemicals, environmental pollutants etc. Morphine is metabolised in vivo typically to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) (McQuay and Moore, www.medicine.ox.ac.uk ). The glucuronide metabolites are formed by the action of the microsomal biotransformation enzymes, uridine-5′-diphosphate (UDP) glucuronyl transferases (UDPGT), mostly in the liver. UGT 2B7 and UGT 1A3 are the major isoenzymes of UDPGT involved in the glucuronidation of morphine. UGT 2B7 primarily produces the 6-conjugate while UGT 1A3 produces the 3-conjugate.However, morphine has a specific affinity for the UGT2B7 isozyme and although in vitro results have indicated a possible role of UGT1A1 in the formation of M3G, in vivo the 2B7 isozyme is the primary morphine metabolite location (Stone et al., 2003). The products of glucuronidation are excreted in the urine and bile. The enzyme reaction leading to metabolite formation is shown in Fig. 7. The M3G and M6G metabolic products account for ~65% of a dose of morphine, with the remaining drug biotransformed to multiple minor species or excreted unchanged (Coffman et al., 1998). Of the two major metabolites, M3G is not analgesic, but plays a role in producing side effects, including the development of clinical tolerance. M6G, on the other hand, exhibits increased potency and the possibility of a better side effect profile compared with morphine (Wittwer and Kern, 2006). Fig. 7. Formation of glucuronide metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) by the action of enzyme, UDP glucuronyl transferase (isoenzyme UGT2B7). Mode of action The analgesic as well as addicting actions of morphine and the opioid drugs are produced upon their binding to receptors located on neuronal cell membranes (Chahl, 1996). Recent studies pertaining to the molecular biology of opioid receptors has shown the involvement of 3 types of receptors in the process: the major receptor μ, and to a lesser extent, δ and k opioid receptors. Morphine has considerably higher affinity for μ receptors than for other opioid receptors (Chahl, 1996). Recent advances in the cloning and characterisation of the opioid receptors have contributed significantly to our understanding of the cellular action of opioids and identification of the sites of action of opioids in the brain. For instance, it is now confirmed that activation of the opioid receptors leads to the observed physiological responses through coupling of the receptors to inhibitory guanine nucleotide-binding regulatory protein (G protein), which then acts through several effectors, including inhibition of adenylyl cyclase, activation of G protein-linked inwardly rectifying K+ channels (GIRKs), and inhibition of voltage-gated Ca2+ channels (Kim et al., 2006). Several types of G-proteins have been found whose specific binding to the opioid receptors produces inhibitory effects in neurons. Opioids essentially act at two sites on the neuron: the presynaptic nerve terminal and the postsynaptic neuron (Chahl, 1996). The major effect of the opioids on the central nervous system (CNS) is the presynaptic action leading to inhibition of neurotransmitter release. The end result of an opioid action in the brain is produced by a combination of both presynaptic and post-synaptic effects. Hence, the overall effect of opioids on a neuron is determined by the location and density of opioid receptors on the neuron. CNS comprises of several types of neurons of different sizes, shapes and the neurotransmitter compounds released by them that carry information to other neurons. Morphine, acting on µ receptors, inhibits the release of several neurotransmitters including noradrenaline, acetylcholine and the neuropeptide, substance P (Chahl, 1996). Pain is evoked by strong mechanical or thermal stimuli, or by chemicals released on account of tissue damage or inflammation, or noxious environmental stimuli (Foulkes and Wood, 2008). The regions of the brain associated with pain perception are extremely complex and involve a number of anatomically defined regulatory pathways. Primary sensory neurons are involved in pain sensation. According to Chahl, “Nociceptive information is transmitted to the brain via the spinothalamic tracts. This ascending information can activate descending pathways, from the midbrain periaqueductal grey area, which exert an inhibitory control over the dorsal horn.” (1996). The opioid drugs act at several levels of the nervous system to produce analgesia. Their action involves inhibition of both the release of neurotransmitter from the primary afferent terminals in the spinal cord and activation of descending inhibitory controls in the midbrain. Opioid inhibition of neurotransmitter releasese Neurotransmitter (mainly glutamate and substance P) release from neurons due to tissue damage is normally preceded by depolarisation of the sensory neurons and Ca++ entry through voltage-sensitive Ca++ channels to propagate action potentials (Chahl, 1996). Analgesic drugs may inhibit neurotransmitter release by acting directly on Ca++ channels to reduce Ca++ entry, or indirectly by increasing the outward K + current, thus shortening repolarisation time and the duration of the action potential. Opioids are able to produce both these effects since opioid receptors are coupled via G-proteins directly to K+ channels as well as voltage-sensitive Ca++ channels. Opioids also interact with other intracellular effector mechanisms, the most important being the adenylate cyclase system. Adenylate cyclase is an enzyme that hydrolyses adenosine triphosphate (ATP) forming cyclic adenosine monophosphate (cAMP). All the 3 types of opioid receptors bind acetyl cyclase, thereby inhibiting neurotransmitter release. Inhibition of neurotransmitter release is believed to be the major mechanism of action through which opioids exert their clinical effects. However, the cellular actions of morphine and other opioids are yet to be fully understood (Chahl, 1996). Many single-nucleotide polymorphism (SNP) affecting pain perception have been identified, the best-characterised being the SNPs present in COMT, the gene coding for catechol-O-methyltransferase (COMT). COMT mediates the inactivation of catecholamine neurotransmitters e.g., dopamine, adrenaline, and noradrenaline. The reduced COMT enzymatic activity appears to result in increased pain sensitivity (Foulkes and Wood, 2008). According to Rakvag et al., “The most studied single nucleotide polymorphism (SNP) in the COMT gene is the Rs4680, also known as Val158Met. This polymorphism causes a substitution from a valine (Val) to a methionine (Met) at amino acid position 158, leading to a three- to four-fold reduced activity of the COMT enzyme.” (2008, p.64). The efficacy of analgesic action of morphine is under the control of several polymorphic genes regulating metabolizing enzymes, transporters, receptors and signal transduction elements which partly account for the observed interindividual variation in pain relief (Campa et al., 2007). Two such genes are ABCB1/MDR1, a major determinant of morphine bioavailability, and OPRM1, which encodes for the µ opioid receptor, the primary site of action for morphine. Polymorphisms in genes coding for the OPRM1 could be important modulators of opioid efficacy since an interaction of multiple genes, rather than a single gene by itself, influences the clinical efficacy of opioids (Reyes-Gibby et al., 2007). The biotransformation enzymes including CYP isoenzymes (phase I) and UGT2B7 (phase II) metabolizing morphine and other opioids are subject to genetic polymorphism. UGT2B7 reactivity with the opioids leads to the production of clinically relevant metabolites viz., M3G, M6G and codeine-6-O-glucuronide. As regards UGT2B7 polymorphism, two UGT2B7 variants with a substitution of tyrosine for histidine at codon 268 have been classified as UGT2B7(Y) and UGT2B7(H), respectively (Coffman et al., 1998). Hence, therapeutic ineffectiveness of these compounds may occur, depending on polymorphism and the substance. Also, the primary site of action of morphine and other commonly used opioid analgesics being the µ-opioid receptor which is a G-protein-coupled receptor, allelic variants, contributing to variations in µ-opioid receptor densities, can lead to changes in opioid response (Ross et al., 2005). Furthermore, according to Ross et al., “the genotype and haplotype frequencies of 26 SNPs across four candidate genes…… (can be) hypothesised to influence response to morphine across different ethnic populations.” (2005, p.331). References Campa, D, Gioia, A, Tomei, A, Poli, P & Barale. R 2007, ‘Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief’, Clinical Pharmacology & Therapeutics advance online publication 26 September 2007; doi:10.1038/sj.clpt.6100385. Chahl, LA 1996, ‘Opioids - mechanisms of action’, Australian Prescriber, vol.19, pp.63- 65. Viewed 22 April, 2009 < http://www.australianprescriber.com/magazine/19/3/63/5/> Coffman, B, King, C, Rios, G & Tephly, T 1998,  ‘The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268)’, Drug Metabolism & Disposition, vol. 26, pp.73-77. Viewed 24 April, 2009, Foulkes T & Wood JN 2008, ‘Pain Genes’, PLoS Genetics, vol. 4, no.7, e1000086. doi:10.1371/journal.pgen.1000086. Viewed 22 April, 2009 McQuay, HJ & Moore, RA, ‘Opioid problems, and morphine metabolism and excretion’, Viewed 22 March, 2009 Rakvåg, T, Ross, JR, Sato, H, Skorpen, F et al. 2008, ‘Genetic variation in the Catechol- O-Methyltransferase (COMT) gene and morphine requirements in cancer patients with pain’, Molecular Pain, vol. 4, 64. Reyes-Gibby, CC, Shete, S, Rakvåg, T, Bhat, SV, Skorpen, F et al. 2007, ‘Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene’, Pain, vol.130, no.1-2, pp. 25-30. Viewed 22 April, 2009 Ross, JR, Rutter, D, Welsh, K, Joel, SP et al. 2005, ‘Clinical response to morphine in cancer patients and genetic variation in candidate genes’, The Pharmacogenomics Journal, vol. 5, pp.324–336. Viewed 25 April, 2009 Stone, A, Mackenzie, P, Galetin, A, Houston, J & Miners, J 2003,  ‘Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human UDP- glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7’, Drug Metabolism & Disposition, vol. 31, pp. 1086-1089. Viewed 24 April, 2009 Wittwer E & Kern SE 2006, ‘Role of Morphine’s Metabolites in Analgesia: Concepts and Controversie’, AAPS Journal, vol. 8, no.2, E348-E352. DOI:  10.1208/aapsj080239 Viewed 24 April, 2009 < http://www.aapsj.org/view.asp?art=aapsj080239> Read More