| | Effects of variation in the human α2A- and α2C-adrenoceptor genes on cognitive tasks and pain perceptionReceived 28 November 2008; received in revised form 29 March 2009; accepted 4 April 2009. published online 08 May 2009. Abstract BackgroundThe 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. ConclusionThe 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. 1. Introduction  Adrenergic signaling plays an important role in cognition. Processes such as memory, learning, and selective attention are influenced by ascending dorsal noradrenergic bundles from the locus ceruleus in the brainstem where α2-adrenoceptors (α2-ARs) play an important role. Also, in the frontal lobe, α2-ARs mediate increased attention (Coull, 1994, Milstein et al., 2007). The noradrenergic system is also intimately involved in pain perception; descending noradrenergic fibers to the spinal cord from the locus ceruleus and brainstem modulate pain responses via spinal α2-ARs (Kwiat and Basbaum, 1992, Proudfit, 1988). There are three α2-ARs subtypes: 2A, 2B and 2C. Studies performed in genetically modified animals have elucidated the specific functions of each α2-AR subtype. In mice, the α2A-AR subtype is the chief mediator of central effects such as sedation and analgesia (Galeotti et al., 2004); however, α2C-ARs also have central effects and alter cortical arousal (Puolivali et al., 2002), amphetamine-induced responses, prepulse inhibition, startle responses (Scheinin et al., 2001), and spatial and non-spatial search patterns (Bjorklund et al., 1999). Both α2A- and α2C-AR subtypes mediate effects at the spinal level (Pieribone et al., 1994), but importantly, α2C-ARs are mainly found on the presynaptic terminals where they inhibit the release of neurotransmitters and mediate spinal analgesia (Fairbanks et al., 2002). Less is known about the specific roles of α2A- and α2C-ARs in mediating central and spinal effects in humans. Effects in the spinal cord are mediated by α2A- and α2B-subtypes, and those in dorsal root ganglia by α2B- and α2C-subtypes (Ongioco et al., 2000, Smith et al., 1995). In humans, non-selective agonists with greater effects at α2C-ARs, for example clonidine, specifically disrupt performance of tasks requiring attention, suggesting that the α2C-AR subtype mediates some specific central effects in humans (Jakala et al., 1999). The lack of subtype-specific agonists and antagonists has made it difficult to further delineate the pharmacological effects mediated by the α2-AR subtypes in humans. The identification of common α2-AR genetic variations that affect receptor function may provide a novel means for defining the functions of the respective subtypes. A common 12 base-pair deletion in the coding region of the α2C-AR gene (ADRA2C) results in the deletion of four amino acids (del322–325) and a receptor that has markedly decreased agonist-mediated responses in vitro (Small et al., 2002). In a previous study, we showed that this variant affected heart rate responses to a cold pressor stimulus. (Kurnik et al., 2008a) The mechanisms underlying this effect are not known. Cold-induced pain is highly heritable, suggesting that it is strongly affected by genetic factors (Nielsen et al., 2008). In view of the central role of α2A- and α2C-ARs in pain perception we addressed the hypotheses that (1) the ADRA2C deletion variant affects cold pressor pain perception and cognitive responses, and (2) other genetic variants in ADRA2A and ADRA2C contribute to interindividual variation in cold pain perception. To augment potential genotypic differences in response, we also repeated the cold pressor test after the administration of dexmedetomidine, a highly selective α2-adrenergic agonist. 2. Methods 2.1. Subjects The study was approved by the Institutional Review Board of Vanderbilt University, and all subjects gave written informed consent. The recruitment process and study procedures are described in detail elsewhere (Kurnik et al., 2008a, Kurnik et al., 2008b). We studied 73 (37 Caucasian and 36 African–American) healthy subjects who were recruited by advertisement and from a volunteer database (Harris et al., 2005). Sixty-seven subjects were enrolled without knowledge of their ADRA2C genotype, and in order to enrich the homozygous subgroups in the study population, six African–American subjects were enrolled because they were known from a previous study to be homozygous for the ADRA2C insertion or deletion allele (three each with Ins/Ins and Del/Del genotype, respectively). 2.2. Study procedure Subjects were studied on two consecutive study days starting in the morning (between 8:00 and 10:00 am) in a temperature-controlled room (22 °C) at the Vanderbilt University Clinical Research Center, after an overnight fast. On study day 1, following a 30min supine rest period, a cold pressor test was performed as previously described (Kurnik et al., 2008a). Briefly, with the participant supine, the left foot was immersed up to the ankle in a tub filled with a slurry of ice and water (4°C) for 2min. Pain ratings were obtained immediately after the foot was withdrawn. On study day 2, each subject received a total of six infusions, three each of saline and dexmedetomidine (0.10, 0.15, and 0.15μg/kg), in that order. The duration of each infusion was 10min with 20min between any two successive infusions. Dexmedetomidine, the most selective α2-adrenergic receptor agonist in clinical use, was administered with the objective of enhancing any differences in response between subjects with different α2-adrenergic receptor genotypes by examining responses under conditions of receptor stimulation. Thirty minutes after completion of the last dexmedetomidine infusion (cumulative dose, 0.4μg/kg), another cold pressor test was performed. The hemodynamic responses in these subjects have been reported previously (Kurnik et al., 2008a). A standardized short term memory test (immediate serial recall), digit symbol substitution test (DSST) (Lezak, 1982), and reaction time tests (Jakala et al., 1999), were administered at the beginning of study day 2 (10min before the start of the first saline infusion) and then 10min after the completion of each of the three saline and three dexmedetomidine infusions. For immediate serial recall, a classic short term memory test, a list of 15 words was read to the subject, who then recalled as many as possible in any order. The DSST is a timed, written test that requires the subject to translate numbers into symbols using a key. DSST performance reflects psychomotor speed, attention, and perceptual organization (Hindmarch, 1980). The computer-based simple reaction time tests and choice reaction time test assesses motor performance as well as sustained attention and vigilance (Jakala et al., 1999). In addition, each subject reported the subjective intensity of sedation at each of these seven time points by placing a mark on a 10cm visual analog sedation scale (VAS), with 0 and 10cm representing no and full sedation, respectively. Similarly, pain response to the cold pressor tests before (study day 1) and after dexmedetomidine (study day 2) was measured using a 10cm visual analog scale. On each study day, one subject did not perform the cold pressor test and was excluded from the analysis of cold pressor test data, but included in other analyses. Blood for the determination of plasma dexmedetomidine concentrations was drawn 10min after the completion of the last dexmedetomidine infusion. 2.3. Genotyping procedure We determined genotypes for five common (estimated minor allele frequency>10%) ADRA2C variants that were not highly linked (linkage disequilibrium r2<0.70: ADRA2C 322–325 ins/del, rs9790683, rs13118771, rs2416, and rs7434444 (Small et al., 2004)) and nine relatively common ADRA2A variants (rs11195418, rs1800544, rs2484516, rs1800545, rs1800035, rs1800038, +1483T>A, rs553668, and rs3750625) (Kurnik et al., 2006). Genotyping for the ADRA2C deletion involved amplification of DNA fragments by polymerase chain reaction (PCR) followed by DNA fragment analysis (Kurnik et al., 2007). The remaining ADRA2C variants and all ADRA2A variants were genotyped by allelic discrimination with TaqMan 5′-nuclease assays (Livak, 2003) on an ABI 7900 HT real-time polymerase chain reaction system (Applied Biosystems, Foster City, California, USA) using validated TaqMan probes and a 95% quality value threshold. For each variant, genotype results were confirmed by direct sequencing in 17–20 randomly selected samples with complete concordance. 2.4. Dexmedetomidine determination Plasma dexmedetomidine concentrations were measured by reversed-phase high-performance liquid chromatography with tandem mass spectrometric detection (LC–MS/MS; SCIEX API 365 instrument, Foster City, CA, USA). The method was modified from a recently published procedure (Ji et al., 2004). The lower limit of quantitation of the assay was 0.02ng/mL. The within- and between-run precision of the assay (coefficient of variation) was within 8% in the relevant concentration range. Dexmedetomidine concentrations could not be determined in three subjects due to technical problems. 2.5. Data and statistical analysis Data are expressed as mean and standard deviation. Comparisons of demographic variables and study outcomes among genotypes were performed by Chi-square test, independent t-test, and one-way analysis of variance, or Mann Whitney U and Kruskal–Wallis test if the normality assumption was not met. Multiple linear regression models were used to assess effects of genetic variants on pain perception and, for ADRA2C del322–325, on cognitive and sedation scores and on choice reaction time, after saline and dexmedetomidine administration. A response-feature approach was used to model multiple measurements on the same patients (Dupont, 2002). In these analyses, the response feature was the area under the score–time curve (AUC) for memory, digit symbol substitution, VAS sedation, and choice reaction time test, which was calculated for each subject as a summary measure of responses during saline (saline AUC) and dexmedetomidine infusion (dexmedetomidine AUC). Previous study showed that only homozygous deletion carriers were functionally different from carriers of an insertion allele (Kurnik et al., 2008a, Small et al., 2002); therefore, we combined subjects who were homozygous (Ins/Ins) or heterozygous (Ins/Del) for the ADRA2C 322–325 insertion allele for analysis. An additive effect was assumed for all other genetic variants. Since ADRA2C and ADRA2A are each partitioned into 10–12 complex haplotypes, our sample size did not allow for formal haplotype analysis, and we restricted our exploratory analysis to single marker analyses. In addition, in view of the exploratory nature of the study, we did not adjust for multiple comparisons. In a sensitivity analysis, we repeated the analysis for pain perception after excluding the six subjects pre-selected by known genotype and after excluding white subjects, since the frequency of the deletion allele is about 10-fold higher in African–Americans than in Caucasians. All statistical models were adjusted for age, race, and sex; in addition, adjustment for plasma dexmedetomidine concentrations was included in models that assessed responses after dexmedetomidine administration. Control (saline) outcome measures were included as covariates in models that assessed changes in responses after dexmedetomidine administration. 3. Results 4. Discussion Our study is the first to examine the effect of genetic variation in two adrenergic receptors (α2C- and α2A-ARs) on pain perception. Our major finding is that the ADRA2C del322–325 genotype is associated with increased pain perception both at baseline and after the administration of the selective α2-AR agonist, dexmedetomidine. However, ADRA2C del322–325 genotype was not associated with short term memory, sedation, and a choice reaction time test during placebo, nor did it influence the effects of dexmedetomidine on these outcomes. None of the other ADRA2C or ADRA2A variants were consistently associated with cold pain sensitivity. Little is known about the role of α2C-ARs in man, but studies in animals suggest that α2C-ARs have both cortical and spinal effects (Bjorklund et al., 1999, Pieribone et al., 1994, Puolivali et al., 2002, Scheinin et al., 2001). Modulation of pain occurs at both spinal and supraspinal levels, and α2C-ARs in the spinal cord and the brain are thought to play a role. In our study, the ADRA2C genotype affected pain perception in response to the cold stimulus but did not affect cortical responses to α2-AR activation, suggesting an important role of spinal α2C-ARs in the modulation of pain perception during the cold pressor test. The effect of the α2C-AR deletion genotype on pain perception was also present after dexmedetomidine, but the change in pain score was not significantly influenced by the genotypes, suggesting that the ADRA2C genotype did not modulate the analgesic effect of dexmedetomidine. The exact mechanisms through which pain perception could be modulated by the ADRA2C deletion variant are not known. The ADRA2C deletion variant encodes a receptor with a loss-of-function phenotype in vitro, and thus would be expected to be associated with increased neurotransmitter release from the presynaptic nerve terminals and to decreased postsynaptic α2C-AR mediated effects. There is evidence that the postsynaptic α2C-AR mediated effects predominate at the spinal level (Stone et al., 1998). Both α2A-ARs and α2C-ARs are thought to be important mediators of α2-AR mediated spinal analgesia (Holmberg et al., 2003). In animal studies, α2C-AR activation in ADRA2A knockout mice resulted in significant anti-nociceptive responses (Fairbanks et al., 2002). Thus, the ADRA2C deletion variant, given its loss-of-function effect, would be expected to be associated with decreased spinal analgesia. Our findings that subjects with ADRA2C Del/Del genotype had significantly higher pain scores in response to the cold pressor test are concordant with that notion. The α2C-AR mediates cold-induced vasoconstriction, and it is conceivable that the ADRA2C deletion variant results in enhanced peripheral vasoconstriction and, through this mechanism, increased pain in response to cold. We addressed this hypothesis in a different study using laser Doppler to measure skin blood flow in response to a graded decrease in temperature and found no effect of the ADRA2C Ins/Del variant on local vascular responses to cold (Friedman et al., in press). Multiple variants in ADRA2C have been described, forming complex haplotypes that affect receptor expression (Small et al., 2004). However, except for the deletion variant, the functional consequences of these individual variants have not been studied. In addition, only a few variants are common and in low linkage disequilibrium (Small et al., 2004). We restricted our analysis to these five variants and found only the deletion variant to be associated with cold pain perception. In addition, none of the ADRA2A SNPs was consistently associated with pain perception. Importantly, in vitro and in vivo functions of ADRA2A variants have been poorly characterized. Thus, our findings suggest either a lack of a functional effect of these ADRA2A variants or a limited role of α2A-ARs in cold pressor pain perception. The α2C-AR has been shown to affect various measures of cognition in mice (Bjorklund et al., 1999, Puolivali et al., 2002, Scheinin et al., 2001), but the role of the α2C-ARs in mediating alertness and other cortical responses in humans is unknown. In our study, dexmedetomidine had significant central effects as evidenced by its effects on sedation, memory, and reaction time. However, central responses to dexmedetomidine were unrelated to the ADRA2C del322–325 genotype, suggesting that this genetic variation in the α2C-AR does not contribute substantially to these responses in humans. Several studies examining experimental pain perception found greater sensitivity to cold pain in blacks than in whites (Rahim-Williams et al., 2007, Kim et al., 2004a), and also in women compared to men (Dixon et al., 2004, Kim et al., 2004b, Compton et al., 2003). We studied healthy volunteers who were free of any medication and had no history of psychiatric illness, under tightly controlled conditions (including standardized diet and salt intake), and found no ethnic or gender differences. Possible reasons for differing findings among studies include methodological differences (for example, many studies did not standardize diet or adjust for covariates). Our study had some limitations. We studied healthy subjects rather than subjects with chronic pain, thus our findings would need to be tested in that population. However, studying healthy subjects allows for a more homogeneous study population with less potential confounding by diseases and their treatment. Although there is a strong genetic component in pain response to the cold pressor test (Nielsen et al., 2008), other pain modalities may be affected by different genetic components (Nielsen et al., 2008), and therefore our findings cannot be automatically extrapolated to other pain models. Also, we addressed the effect of the ADRA2C and ADRA2A variants in a hypothesis-driven fashion and thus did not address the potential role of other genetic factors that could alter pain perception and interact with the ADRA2C del322–325 variant. In addition, considering the complexity of ADRA2C and ADRA2A haplotypes, our sample size did not allow a formal haplotype analysis. In summary, we report that the common ADRA2C del322–325 variant is associated with pain perception both at baseline and after administration of the α2-AR agonist dexmedetomidine but not with other centrally mediated α2-AR responses such as sedation, memory, and reaction time. Further studies in other experimental pain models and larger populations will be of interest. 4.1. Funding sources 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. 4.2. Disclosures The laboratory of Mika Scheinin has contract research relationships with Orion Corporation (Espoo, Finland) and Hospira (Lake Forest, IL, USA). Hospira has a license agreement with Orion Corporation concerning dexmedetomidine (Precedex®). Mika Scheinin has also received speaker fees and consulting fees from Orion Corporation. None of the other authors has a conflict of interest relevant to the work presented. 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