Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence.

Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Research Abstract Details 

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Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Abstract Text:

De-Yong Liang,Guochun Liao,Geoff K Lighthall,Gary Peltz,David J Clark,

OBJECTIVE: Opioid-induced hyperalgesia (OIH) is a state of paradoxically increased nociceptive sensitivity seen in both humans and rodents following the resolution of the acute opioid antinociceptive effects or during periods of chronic opioid administration. Using the power of genetic analysis, we hoped to discover novel mechanisms modulating this trait. BASIC METHODS: The degree of opioid-induced hyperalgesia displayed in response to a thermal stimulus applied to the hind paw was measured in 16 strains of inbred mice after 4 days of morphine administration. The degree of thermal sensitization was then used in a recently developed in silico haplotypic mapping algorithm along with a haplotypic map constructed from a database containing 209,000 single nucleotide polymorphisms. MAIN RESULTS: Analysis of the data resulted in the identification of several haplotype blocks strongly associated with the thermal opioid-induced hyperalgesia trait. The most strongly associated block was located within the Abcb1b P-glycoprotein drug transporter gene. Experiments using the P-glycoprotein inhibitor cyclosporine A and P-glycoprotein null mutant mice supported the hypothesis that a functional association exists between P-glycoprotein transporters and opioid-induced hyperalgesia. The observation of a correlation between morphine brain concentrations and the development of opioid-induced hyperalgesia was consistent with this hypothesis as well. In addition, P-glycoprotein gene deletion and pharmacological inhibition altered morphine ED50, tolerance and physical dependence. CONCLUSIONS: We conclude that the use of haplotypic mapping to identify novel mechanisms controlling complex traits is a viable approach. Variants of the Abcb1b gene may explain some portion of the interstrain differences in OIH and perhaps other consequences of chronic opioid administration.

Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Publishing Authors By Initials

DY Liang,G Liao,GK Lighthall,G Peltz,DJ Clark,

For similar genetic phenomena: variation (genetics) research abstracts see: genetic phenomena: variation (genetics) research

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MEDLINE DATE:

Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Pharmacogenetics and genomics

VOLUME: 16

Page Numbers: 825-35

Journal Abbreviation: Pharmacogenet. Genomics

ISSN: 1744-6872

DAY: 3

MONTH: Nov

YEAR: 2006

Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101231005

Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Keywords Mesh Terms:

KEYWORDS: Variation (Genetics)

MESH TERMS: genetics

Chemical & Substance for Abstract: Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Information

Substance Name: Morphine

Registry Number: 57-27-2

Grant and Affiliation Information for Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence.

AFFILIATION: Department of Anesthesiology, Stanford University, California, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM068885-01A1

ACRONYM: GM

MEDLINETA: Pharmacogenet Genomics

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