Effects of variation in the human α2A- and α2C-adrenoceptor genes on cognitive tasks and pain perception

Utkarsh Kohli, Mordechai Muszkat, Gbenga G. Sofowora, Paul A. Harris, Eitan A. Friedman, William D. Dupont, Mika Scheinin, Alastair J.J. Wood, C. Michael Stein, Daniel Kurnik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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 ± 4.6 years. Pain response to a cold pressor test was measured using a 10 cm 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 ± 1.8 cm) and after dexmedetomidine (5.6 ± 2.2 cm) than insertion allele carriers (4.6 ± 2.1 cm [baseline] and 3.8 ± 1.9 cm [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.

Original languageAmerican English
Pages (from-to)154-159
Number of pages6
JournalEuropean Journal of Pain
Issue number2
StatePublished - Feb 2010
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported in part by US Public Health Service grants, M01 RR-00095 from the National Center for Research Resources, P01 HL56693, GM31304, a Pharmacogenetics Research Network Grant (U01 HL65962), and a Vanderbilt CTSA Grant 1 (UL1 RR024975) from the National Center for Research Resources, National Institutes of Health. Drs. Kurnik and Muszkat were recipients of a Merck Sharp & Dohme International Fellowship in Clinical Pharmacology.


  • Cognition
  • Genetics
  • Pain
  • α-adrenoceptor
  • α-adrenoceptor


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