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


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.


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.
Liang
De-Yong
DY
Department of Anesthesiology, Stanford University, California, USA.
Liao
Guochun
G
Lighthall
Geoff K
GK
Peltz
Gary
G
Clark
David J
DJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D000701:Analgesics, Opioid / Q000009:adverse effects; D000818:Animals; D001923:Brain Chemistry; D002874:Chromosome Mapping; D004361:Drug Tolerance / Q000235:genetics*; D017353:Gene Deletion; D014644:Genetic Variation; D006239:Haplotypes; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics; D010147:Pain Measurement; D019966:Substance-Related Disorders / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D009020:Morphine