Efficacy Of Opioid Antagonists Research Articles

Antagonist Efficacy in MORS196L Mutant Is Affected by the Interaction between Transmembrane Domains of the Opioid Receptor

In a previous study, we demonstrated that antagonists such as naloxone or naltrexone acted as full agonists at the mu-opioid receptor (MOR)/delta-opioid receptor (DOR) chimeric receptor (mudelta2, where the DOR sequence from the first extracellular loop to the carboxyl terminus was spliced to the MOR sequence) when a conserved serine residue in transmembrane 4 (TM4) was mutated to leucine. However, when Ser196 in the TM4 of MOR was mutated to Leu, antagonists exhibited partial agonistic properties. Since molecular modeling studies suggested transmembrane movement during receptor activation, the observed partial agonistic properties could be due to TM1 and TM7 interaction. Hence, MOR/DOR chimeric mutant receptors with the MOR TM1 and TM7 sequence (mudelta2mu7S196L) or with the MOR TM1 and TM6/7 sequence (mudelta2mu67S196L) were constructed to test such a hypothesis. Using four tests of opioid receptor activation, we found that the opioid antagonists were full agonists in chimeric mutant receptor if the TM1 and TM7 were from different opioid receptors. Additionally, when two of the TM7 amino acid residues of MORS196L receptor mutants were mutated (T327A and C330S), resulting in a mutant receptor with DOR TM7 sequence, opioid antagonist naloxone exhibited full agonistic properties. These data suggest that the efficacy of opioid antagonists in the Ser196 mutant can be affected by the interaction between TM1 and TM7.

Treatment of compulsive sexual behaviour with naltrexone and serotonin reuptake inhibitors: two case studies

Although there is no universally accepted definition of compulsive sexual behaviour (CSB), the term is generally used to indicate excessive sexual behaviour or sexual cognitions that lead to subjective distress, social or occupational impairment, or legal and financial consequences. Similar to impulse control disorders, CSB is characterized by a failure to resist the impulse for sex. Opioid antagonists have been effective in treating urge-driven disorders, such as pathological gambling disorder, alcoholism, borderline personality disorder with self-injurious behaviour, cocaine abuse, mental retardation with self-injurious behaviour and eating disorders. Based upon the efficacy of opioid antagonists in treating disorders associated with urges, we hypothesized that naltrexone would reduce both the urges associated with CSB and therefore reduce the sexual behaviour. We present two case reports of individuals with CSB treated successfully with naltrexone, a novel treatment for CSB. In both cases, symptoms dramatically decreased and psychosocial functioning improved with the use of naltrexone. Although more research is needed to determine the mechanism that leads to the excessive sexual behaviour in individuals with CSB, the present case reports suggest that naltrexone may be effective in treating some cases of CSB.