Hi, need to submit a 1250 words paper on the topic Molecular and Biochemical Mechanisms of Analgesic Response to Morphine and Other Opioids. 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 metabolized 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). .
The analgesic as well as the addicting actions of morphine and the opioid drugs are produced upon their binding to receptors located on neuronal cell membranes (Chahl, 1996).