From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics.
paper
Cited
Public
- Authors
- Chu, Larry F; Liang, De-Yong; Li, Xiangqi; Sahbaie, Peyman; D'arcy, Nicole; Liao, Guochun; Peltz, Gary; David Clark, J
- Year
- 2009
- Journal
- Pharmacogenetics and genomics
- PMID
- 19214139
- DOI
- 10.1097/FPC.0b013e328322e73d
- PMCID
- PMC2730361
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.
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| 0.9% saline solution local | drug |
| 129/SvlmJ local | cohort |
| 129_SVLMJ local | cohort |
| 129/SvlmJ mice local | cohort |
| 5-HT3 antagonists local | drug |
| 5-HT3 receptor | drug |
| actin | drug |
| addiction | phenotype |
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| A/J local | cohort |
| AKR/J local | cohort |
| amygdala | anatomy |
| analgesic response | phenotype |
| Animal behavioral data local | phenotype |
| anxiety | phenotype |
| Aversive Behavior (light/dark exploration) local | phenotype |
| B10.D2-H2/oSNJ local | cohort |
| BALB/cByJ local | cohort |
| BALB/cJ local | cohort |
| benzodiazepines | drug |
| bipolar disorder | phenotype |
| brain | anatomy |
| brainstem | anatomy |
| brainstem nuclei | anatomy |
| BUB/BnJ local | cohort |
| buprenorphine | drug |
| C3ar1 local | gene |
| C3H/HeJ local | cohort |
| C57BL/6J | cohort |
| C57BL_6J local | cohort |
| C5ar1 local | gene |
| cerebellum | anatomy |
| chronic opioid use | phenotype |
| chronic pain | phenotype |
| chronic pain management patients local | cohort |
| clonidine local | drug |
| CNS | anatomy |
| CO2 | drug |
| cocaine | phenotype |
| codeine | drug |
| conditioned place aversion | phenotype |
| conditioned place preference | phenotype |
| Conditioned_place_preference local | phenotype |
| cortex | anatomy |
| CPP data local | phenotype |
| DBA/2J | cohort |
| dependence | phenotype |
| Dependence liability local | phenotype |
| depression | phenotype |
| Dithiothreitol | drug |
| dorsal raphe nucleus | anatomy |
| drug dependence | phenotype |
| ethanol consumption | phenotype |
| female volunteers local | cohort |
| flu-like symptoms local | phenotype |
| FVB/NJ local | cohort |
| gastrointestinal disorder local | phenotype |
| gene | gene |
| haplotype block | variant |
| healthy male volunteers local | cohort |
| heavy drinking | phenotype |
| Heroin_self_administration local | phenotype |
| Hexamers local | drug |
| high withdrawal-induced jumping behavior local | phenotype |
| Htr3a | gene |
| HTR3A variant local | variant |
| Htr3b | gene |
| HTR3B functional variant local | variant |
| HTR3B variant local | variant |
| Human homolog of murine gene local | gene |
| Human volunteers local | cohort |
| Human_volunteers local | cohort |
| hyperalgesia | phenotype |
| inbred strains | cohort |
| isoflurane | drug |
| Jumping behavior local | phenotype |
| Jumping Behavior local | phenotype |
| Kcnj6 | gene |
| laser-captured RNA local | drug |
| LG/J local | cohort |
| liquid nitrogen | drug |
| low withdrawal-induced jumping behavior local | phenotype |
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| mesolimbic system | anatomy |
| Methadone | drug |
| mice | cohort |
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| morphine | drug |
| Morphine-dependent mice local | cohort |
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| mRNA | drug |
| Murine gene local | gene |
| naloxone | drug |
| NALOXONE_INDUCED_JUMPING local | phenotype |
| Naloxone-induced withdrawal behavior local | phenotype |
| Naloxone-precipitated jumping local | phenotype |
| NALOXONE_PRECIPITATED_WITHDRAWAL local | phenotype |
| narcotic drug | drug |
| Narcotic_withdrawal_symptoms local | phenotype |
| nausea | phenotype |
| Nausea after antidepressant administration local | phenotype |
| nicotine | drug |
| Nociceptive sensitization local | phenotype |
| Nociceptive testing local | phenotype |
| Nylon von Frey filaments local | drug |
| NZB/BinJ local | cohort |
| NZW/LaCJ local | cohort |
| Objective Opioid Withdrawal scale local | phenotype |
| objective opioid withdrawal scale (OOWS) local | phenotype |
| ondansetron | drug |
| Ondansetron-treated group local | cohort |
| OOWS local | phenotype |
| opioid | drug |
| Opioid_cravings local | phenotype |
| opioid dependence | phenotype |
| opioid-induced hyperalgesia | phenotype |
| opioid narcotic drug responses local | phenotype |
| opioid narcotic drugs local | drug |
| opioid narcotics local | drug |
| Opioid narcotics local | drug |
| opioid response | phenotype |
| opioid tolerance | phenotype |
| opioid withdrawal | phenotype |
| Opioid_withdrawal local | phenotype |
| Optimal cutting temperature medium local | drug |
| oxycodone | drug |
| pain | phenotype |
| patients | cohort |
| PCR | drug |
| periaqueductal gray | anatomy |
| Periquaductal gray nuclei local | anatomy |
| persons aged 12 years or older local | cohort |
| physical dependence | phenotype |
| Physical dependence on opioids local | phenotype |
| PicoPure (Arcturus) RNA spin column purification kit local | drug |
| Place_aversion local | phenotype |
| Placebo-treated group local | cohort |
| poor concentration local | phenotype |
| prescription pain relievers local | drug |
| random hexamer primers local | drug |
| Reinforcing properties of morphine local | phenotype |
| reverse transcription local | drug |
| RiboAmp RNA amplification kit (Arcturus) local | drug |
| RNase H | drug |
| RNasin local | drug |
| rRNA | drug |
| saline | drug |
| sensitization to cocaine local | phenotype |
| SEVERITY_NALOXONE_WITHDRAWAL local | phenotype |
| single nucleotide polymorphism | variant |
| SM/J local | cohort |
| SOWS local | phenotype |
| spinal cord | anatomy |
| SPINAL_CORD local | anatomy |
| Subjective Opioid Withdrawal scale local | phenotype |
| subjective opioid withdrawal scale (SOWS) local | phenotype |
| SuperScript II | drug |
| SYBR green | drug |
| tachycardia | phenotype |
| tolerance | phenotype |
| ventricles | anatomy |
| vital signs | phenotype |
| withdrawal | phenotype |
| withdrawal-induced jumping behavior local | phenotype |
| xylene | drug |
| young adults | cohort |
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