Effects of variation in the human α2A- and α2C-adrenoceptor genes on cognitive tasks and pain perception
Received 28 November 2008; received in revised form 29 March 2009; accepted 4 April 2009. published online 08 May 2009.
Abstract
Background
The mechanisms underlying interindividual variability in pain perception and cognitive responses are undefined but highly heritable. α2C- and α2A-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 α2-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).
Conclusion
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.
aDepartments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
bDepartment of Biomedical Informatics and Engineering, Vanderbilt University, USA
cDepartment of Biostatistics, Vanderbilt University, USA
dDepartment of Pharmacology, Drug Development, and Therapeutics, University of Turku, Finland
eDepartment of Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland
fDivision of Clinical Pharmacology, Department of Medicine, Chaim Sheba Medical Center, Ramat Gan, Israel
gSackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Corresponding author. Address: Division of Clinical Pharmacology and Toxicology, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel. Tel.: +972 3 530 2358; fax: +972 3 535 1596.
ABSTRACT