OBJECTIVES: Addiction to opioid narcotics represents a major public health challenge. Animal models of one component of addiction, physical dependence, show this trait to be highly heritable. The analysis of opioid dependence using contemporary in-silico techniques offers an approach to discover novel treatments for dependence and addiction. METHODS: In these experiments, opioid withdrawal behavior in 18 inbred strains of mice was assessed. Mice were treated for 4 days with escalating doses of morphine before the administration of naloxone allowing the quantification of opioid dependence. After haplotypic analysis, experiments were designed to evaluate the top gene candidate as a modulator of physical dependence. Behavioral studies as well as measurements of gene expression on the mRNA and protein levels were completed. Finally, a human model of opioid dependence was used to quantify the effects of the 5-HT3 antagonist ondansetron on signs and symptoms of withdrawal. RESULTS: The Htr3a gene corresponding to the 5-HT3 receptor emerged as the leading candidate. Pharmacological studies using the selective 5-HT3 antagonist ondansetron supported the link in mice. Morphine strongly regulated the expression of the Htr3a gene in various central nervous system regions including the amygdala, dorsal raphe, and periaqueductal gray nuclei, which have been linked to opioid dependence in previous studies. Using an acute morphine administration model, the role of 5-HT3 in controlling the objective signs of withdrawal in humans was confirmed. CONCLUSION: These studies show the power of in-silico genetic mapping, and reveal a novel target for treating an important component of opioid addiction.
OBJECTIVES: Addiction to opioid narcotics represents a major public health challenge. Animal models of one component of addiction, physical dependence, show this trait to be highly heritable. The analysis of opioid dependence using contemporary in-silico techniques offers an approach to discover novel treatments for dependence and addiction. METHODS: In these experiments, opioid withdrawal behavior in 18 inbred strains of mice was assessed. Mice were treated for 4 days with escalating doses of morphine before the administration of naloxone allowing the quantification of opioid dependence. After haplotypic analysis, experiments were designed to evaluate the top gene candidate as a modulator of physical dependence. Behavioral studies as well as measurements of gene expression on the mRNA and protein levels were completed. Finally, a human model of opioid dependence was used to quantify the effects of the 5-HT3 antagonist ondansetron on signs and symptoms of withdrawal. RESULTS: The Htr3a gene corresponding to the 5-HT3 receptor emerged as the leading candidate. Pharmacological studies using the selective 5-HT3 antagonist ondansetron supported the link in mice. Morphine strongly regulated the expression of the Htr3a gene in various central nervous system regions including the amygdala, dorsal raphe, and periaqueductal gray nuclei, which have been linked to opioid dependence in previous studies. Using an acute morphine administration model, the role of 5-HT3 in controlling the objective signs of withdrawal in humans was confirmed. CONCLUSION: These studies show the power of in-silico genetic mapping, and reveal a novel target for treating an important component of opioid addiction.
Authors: C A Brady; I M Stanford; I Ali; L Lin; J M Williams; A E Dubin; A G Hope; N M Barnes Journal: Neuropharmacology Date: 2001-08 Impact factor: 5.250
Authors: A L Feldman; N G Costouros; E Wang; M Qian; F M Marincola; H R Alexander; S K Libutti Journal: Biotechniques Date: 2002-10 Impact factor: 1.993
Authors: Benjamin Kest; Eileen Hopkins; Christina A Palmese; Michael Adler; Jeffrey S Mogil Journal: Pharmacol Biochem Behav Date: 2002-11 Impact factor: 3.533
Authors: Kevin C Greer; Abdullah S Terkawi; Siny Tsang; Priyanka Singla; Marcel E Durieux; Mohamed Tiouririne Journal: Reg Anesth Pain Med Date: 2017 Sep/Oct Impact factor: 6.288
Authors: Larry F Chu; Tom Rico; Erika Cornell; Hannah Obasi; Ellen M Encisco; Haley Vertelney; Jamison G Gamble; Clayton W Crawford; John Sun; Anna Clemenson; Matthew J Erlendson; Robin Okada; Ian Carroll; J David Clark Journal: Drug Alcohol Depend Date: 2017-08-14 Impact factor: 4.492
Authors: Larry F Chu; John Sun; Anna Clemenson; Matthew J Erlendson; Tom Rico; Erika Cornell; Hannah Obasi; Zahra N Sayyid; Ellen M Encisco; Jeff Yu; Jamison G Gamble; Ian Carroll; J David Clark Journal: J Addict Med Date: 2017 Sep/Oct Impact factor: 3.702
Authors: José Vicente Lafuente; Aruna Sharma; Dafin F Muresanu; Asya Ozkizilcik; Z Ryan Tian; Ranjana Patnaik; Hari S Sharma Journal: Mol Neurobiol Date: 2018-01 Impact factor: 5.590