Effects of variation in the human alpha2A- and alpha2C-adrenoceptor genes on cognitive tasks and pain perception.
BACKGROUND
The mechanisms underlying interindividual variability in pain perception and cognitive responses are undefined but highly heritable. alpha(2C)- and alpha(2A)-adrenergic receptors regulate noradrenergic activity and are important mediators of pain perception and analgesia. We hypothesized that common genetic variants in these genes, particularly the ADRA2C 322-325 deletion variant, affect pain perception or cognitive responses.


METHODS
We studied 73 healthy subjects (37 Caucasians and 36 African-Americans) aged 25.4+/-4.6years. Pain response to a cold pressor test was measured using a 10cm visual analog scale and again on the next day, after three infusions of the selective alpha(2)-agonist dexmedetomidine. Standardized cognitive tests were administered at baseline and after each infusion. The contribution of ADRA2C deletion genotype, dexmedetomidine concentration, and other covariates to pain perception and cognitive responses was determined using multiple linear regression models. Secondary analysis examined the effects of ADRA2A and other ADRA2C variants on pain perception.


RESULTS
ADRA2C Del homozygotes had higher pain scores in response to cold at baseline (6.3+/-1.8cm) and after dexmedetomidine (5.6+/-2.2cm) than insertion allele carriers (4.6+/-2.1cm [baseline] and 3.8+/-1.9cm [after dexmedetomidine]; adjusted P-values=0.019 and 0.004, respectively). Cognitive responses were unrelated to ADRA2C Ins/Del genotype. None of the other ADRA2A and ADRA2C variants was significantly related to cold pain sensitivity before dexmedetomidine; after dexmedetomidine, ADRA2A rs1800038 was marginally associated (P=0.03).


CONCLUSIONS
The common ADRA2C del322-325 variant affected pain perception before and after dexmedetomidine but did not affect other cognitive responses, suggesting that it contributes to interindividual variability in pain perception.
Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Utkarsh
U
Kohli
Mordechai
M
Muszkat
Gbenga G
GG
Sofowora
Paul A
PA
Harris
Eitan A
EA
Friedman
William D
WD
Dupont
Mika
M
Scheinin
Alastair J J
AJ
Wood
C Michael
CM
Stein
Daniel
D
Kurnik
D000316:Adrenergic alpha-Agonists; D000328:Adult; D003071:Cognition / Q000502:physiology*; D003080:Cold Temperature; D020927:Dexmedetomidine; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000235:genetics* / Q000523:psychology; D010147:Pain Measurement; D011312:Pressure; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
C547768:ADRA2A protein, human; C547774:ADRA2C protein, human; D000316:Adrenergic alpha-Agonists; D006993:Hypnotics and Sedatives; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine