Opioid Receptor Polymorphism Research Articles

Functional and Neural Correlates Associated with Conditioned Pain Modulation in Patients with Chronic Knee Osteoarthritis Pain: A Cross-Sectional Study.

Background: In this study, we aimed to assess the factors that predict a dysfunctional conditioned pain modulation (CPM) in chronic knee OA. Methods: This is a cross-sectional analysis of patients with chronic knee OA from a prospective cohort study in Brazil (n = 85). We performed linear and logistic multivariate regression models using the purposeful selection approach to test the relationship between the CPM in both knees (average) as a dependent variable and demographics, clinical, and neurophysiological as independent variables. Results: A significant negative association between WOMAC pain scores and CPM (β: -0.13) was found. This association was modified by the subjects' race, being stronger in the non-white subjects. In our logistic regression models, pain intensity indexed with the WOMAC pain scale remained a significant association with dichotomized CPM. Furthermore, a significant CPM association with balance, indexed with the Berg Balance score, was evidenced (β: 0.04). Neurophysiological variables showed a significant negative relationship with CPM, such as the relative power of delta oscillations in the frontal area (β: -3.11) and central area (β: -3.23). There was no significant relationship between CPM and the following domains: cognitive, emotion, sleep, opioid receptor polymorphisms, and intrinsic variables of OA disease. There was no association of CPM with TMS-indexed inhibitory markers. Conclusions: These results may indicate that less function of the pain descending inhibitory system in patients with OA is correlated with higher activity-related pain (WOMAC), less balance, and cortical plasticity especially with increased low-frequency (delta) brain oscillations. These associations seem modified by race.

Opioid Receptor-Mediated and Non-Opioid Receptor-Mediated Roles of Opioids in Tumour Growth and Metastasis.

Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour growth and metastasis, and their consequences on disease outcome, continue to be the object of polarised, discrepant literature. It is becoming clear that opioids contribute a range of direct and indirect effects to the biology of solid tumours, to the anticancer immune response, inflammation, angiogenesis and importantly, to the tumour-promoting effects of pain. A common misconception in the literature is that the effect of opioid agonists equates the effect of the mu-opioid receptor, the major target of the analgesic effect of this class of drugs. We review the evidence on opioid receptor expression in cancer, opioid receptor polymorphisms and cancer outcome, the effect of opioid antagonists, especially the peripheral antagonist methylnaltrexone, and lastly, the evidence available of a role for opioids through non-opioid receptor mediated actions.

Association Study of OPRM1 Gene in a Sample of Schizophrenia Patients With Alcohol Dependence or Abuse.

Alcohol use disorder is a complex disorder that is influenced by genetic factors. The non-synonymous single-nucleotide polymorphism (SNP) rs1799971 in exon 1 in opioid receptor OPRM1 was extensively studied in patients with alcohol dependence with mixed findings. Moreover, studies showed that opioid receptor polymorphism might play a role in the pathophysiology of schizophrenia. Our results suggest that rs1799971 SNP is not significantly associated with alcohol dependence in our sample of Schizophrenia patients of European ancestry.

Modelling the PKPD of oxycodone in experimental pain — Impact of opioid receptor polymorphisms

BackgroundPolymorphisms in the opioid receptor genes may affect the pharmacodynamics (PD) of oxycodone and be part of the reason behind the diversity in clinical response. The aim of the analysis was to model the exposure–response profile of oxycodone for three different pain variables and search for genetic covariates. Model simulations were used to predict how population and effect-size impact the power to detect clinical significant SNPs. MethodThe population pharmacokinetic–pharmacodynamic (PKPD) model of oral single-dosed oxycodone was based on pooled data from three published studies in healthy volunteers. Pain tolerance data from muscle pressure (n=36), visceral pressure (n=54) and skin pinch (n=34) were included. Genetic associations with 18 opioid-receptor SNPs were explored using a stepwise covariate approach. Model simulations were performed using the estimated model parameters. ResultsNone of the selected SNPs were associated with analgesic response of oxycodone at P<0.001. Baseline response in muscle cuff pressure was associated with OPRK1 rs7016778 and rs7824175 (P<0.001). Simulations indicated that large differences in drug response between genotypes (>50% for similar population sizes) or large populations (n>200 for a 20% response difference) are necessary to identify clinical significant SNP effects due to high population variability. ConclusionA population PKPD model has been developed for oral oxycodone using three different pain variables to explore impact of genetic covariates and study design. None of the selected polymorphisms were significantly associated with analgesic response of oxycodone, but an association of baseline response in muscle cuff pressure with two OPRK1 SNPs was identified.

Mu opioid receptor polymorphism, early social adversity, and social traits

ABSTRACTA polymorphism in the mu opioid receptor gene OPRM1 (rs1799971) has been investigated for its role in sensitivity to social contexts. Evidence suggests that the G allele of this polymorphism is associated with higher levels of sensitivity. This study tested for main effects of the polymorphism and its interaction with a self-report measure of childhood adversity as an index of negative environment. Outcomes were several personality measures relevant to social connection. Significant interactions were obtained, such that the negative impact of childhood adversity on personality was greater among G carriers than among A homozygotes on measures of agreeableness, interdependence, anger proneness, hostility, authentic pride, life engagement, and an index of (mostly negative) feelings coloring one’s world view. Findings support the role of OPRM1 in sensitivity to negative environments. Limitations are noted, including the lack of a measure of advantageous social environment to assess sensitivity to positive social contexts.

PL.01.01 New targets for the treatment of addiction

I will discuss treatment strategies that are based on pharmacological interventions to reduce craving and relapse in drug and alcohol-dependent patients. I will first provide a historical overview about relapse prevention strategies and will then discuss the current state of the treatment situation in Europe. The presentation will mainly focus on alcohol addiction as major achievements have been made in recent years in the development of anti-relapse drugs and harm reduction in the alcohol field. Thus the development of disulfiram, naltrexone, acamprosate, and nalmefene will be described followed by a discussion of their neurobiological modes of action. This will be followed by a perspective on the introduction of substitution drugs to alcohol addicted patients and the combined use of behavioral and pharmacological interventions such as acceleration of extinction of a drug memory by D-cycloserine or the pharmacological disruption of the reconsolidation of a drug memory. Finally, the use of deep brain stimulation in treatment resistant patients will be discussed. Important conclusions of this lecture are: (i) in Europe there is a paradigmatic shift towards harm reduction in the addiction field, (ii) the substitution concept that is successfully used in opiate and nicotine dependent patients can be also introduced to alcoholic patients, (iii) matching treatment to specific genotypes (e.g. opioid receptor polymorphism) increases treatment success, (iv) a combination of behavioral and pharmacological therapies may be the optimal treatment strategy, and finally (v) the whole organism has to be taken into consideration to provide the best therapy for our patients.

SY18-4 * A PHARMACOGENETIC STUDY OF NALTREXONE IN KOREAN ALCOHOLICS

Introduction. According to a recent pharmacogenetic study, patients with alcohol dependence (AD) who have one or two 118G alleles (G carriers) respond better to naltrexone than those who have the A/A genotype of the A118G mu opioid receptor (G non-carriers). This study was conducted to prospectively investigate the relationship between genotype and response to open label naltrexone treatment in Korean subjects with AD. Methods. Sixty-three subjects with AD were prescribed naltrexone for 12 weeks in combination with cognitive behavioral therapy. Thirty-two subjects were adherent and took the medication on at least 80% of the treatment days (16 G carriers and 16 G non-carriers). Results. The G carriers adherent to the naltrexone treatment took a significantly longer time than the G non-carriers (p = 0.014). The G carriers treated with naltrexone had a 10.6 times greater relapse rate than G non-carriers (p = 0.072). Conclusions. These results demonstrate a higher therapeutic effect of naltrexone in Korean subjects with AD who have one or two 118G alleles compared to those who have the A/A genotype. Considering that Asians are more frequent G carriers for the A118G mu opioid receptor polymorphism than Caucasians, naltrexone might be more effective for treating AD in Asians than Caucasians.

On the Role of Genetic Testing for Personalized Drug Overdose Management

Author Reply: We thank our colleagues for their interest in our study entitled “Opioid Receptor Polymorphism A118G Associated with Clinical Severity in a Drug Overdose Population.” Our results add to the growing literature over the past decade that implicate a handful of promising single nucleotide polymorphisms (SNPs) of the mu opioid receptor gene (OPRM1) as candidates for clinically relevant variability in baseline mesolimbic reward neurobiology (dopamine–opioid interaction), opioid sensitivity, and addiction [1]. Our findings warrant further research to understand the mechanisms underlying specific at-risk overdose populations. We completely concur that results of our pilot study, as with all such investigations, will require validation in larger populations, an effort which is currently being addressed at our institution. Confirming our results would have significant impact in the field of addiction to pave the way for personalized prescription practices not only for opioids, but for those at risk for drug overdose. Our data which demonstrated higher overdose severity in G allele subjects, not limited to opioid drugs, is likely due to dopamine–opioid interactions in the mesolimbic/striatal pathways relevant to reward and habit formation. Indeed, several lines of evidence have established significant disturbances of the opioid system in association with various drugs of abuse [2, 3]. We therefore chose not to limit the analysis to only opioids given the biologic plausibility of enhanced abuse and addiction behaviors which apply for all drugs, not limited to opioids. To address our colleagues’ suggestion to eliminate sympathomimetics, such as cocaine, from the analysis, we would argue that it is equally plausible that OPRM1 variants affect the same reward pathways for sympathomimetics, and thus arbitrary removal of these exposures would actually introduce, not eliminate, bias. A question was also raised as to whether the 118G allele confers resistance rather than increased susceptibility as suggested by the findings of our study. Consistent with the results of our study, multiple investigations have reported an association of the 118G allele with opioid abuse [4–6]. However, the mu opioid receptor is involved in multiple physiological functions, thus the 118G allele could be beneficial for some processes, but adverse for others. Our colleagues also question whether race/ethnicity may have introduced confounding into our analysis. To truly control for the effect of racial bias, it would be necessary to not only gather self-reported data, which is difficult to gather on critically ill patients with altered mental status due to overdose, but also it would be necessary to perform additional analyses such as ancestral informative markers (AIMs), which we did not have available at the time. The poor specificity of racial/ethnic variables in addiction research is often compounded by failure to measure social and environmental exposures that track with self-identified race in the USA, thereby masking important gene–environment effects. Missing these effects means missing an opportunity to disentangle the complex social, environmental, behavioral, and genetic factors that interact to create disease and determine treatment outcomes [7]. To account for this, future studies of OPRM1 variants in overdose populations should gather social and environmental variables as well as perform AIMs analysis.

Opioid receptor polymorphism A118G associated with clinical severity in a drug overdose population.

Genetic variations in the human mu-opioid receptor gene (OPRM1) mediate individual differences in response to pain and opiate addiction. We studied whether the common A118G (rs1799971) mu-opioid receptor single nucleotide polymorphism (SNP) was associated with overdose severity in humans. In addition, we examined an SNP responsible for alternative splicing of OPRM1 (rs2075572). We assessed allele frequencies of the above SNPs and associations with clinical severity in patients presenting to the emergency department (ED) with acute drug overdose. This work was designed as an observational cohort study over a 12-month period at an urban teaching hospital. Participants consisted of consecutive adult ED patients with suspected acute drug overdose for whom discarded blood samples were available for analysis. Specimens were linked with clinical variables (demographics, urine toxicology screens, clinical outcomes) then deidentified prior to genetic SNP analysis. Blinded genotyping was performed after standard DNA purification and whole genome amplification. In-hospital severe outcomes were defined as either respiratory arrest (RA; defined by mechanical ventilation) or cardiac arrest (CA; defined by loss of pulse). We analyzed 179 patients (61% male, median age 32) who overall suffered 15 RAs and four CAs, of whom three died. The 118G allele conferred 5.3-fold increased odds of CA/RA (p<0.05), while the rs2075572 variant allele was not associated with CA/RA. The 118G variant allele in the OPRM1 gene is associated with worse clinical severity in patients with acute drug overdose. These findings mark the first time that the 118G variant allele is linked with clinical drug overdose vulnerability.

Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol

Naltrexone, one of four FDA-approved pharmacotherapies for alcohol dependence, has shown moderate efficacy in clinical trials. Pharmacogenetic effects have been reported such that allelic variation at the gene encoding the mu-opioid receptor (OPRM1, rs1799971) predicts naltrexone-induced blunting of the positively reinforcing effects of alcohol. However, naltrexone also binds, albeit to a lesser degree, to kappa and delta opioid receptors in the brain. This alternate binding presents the possibility that single nucleotide polymorphisms (SNPs) in the kappa and delta opioid receptor (OPRK1 and OPRD1) genes may contribute to naltrexone pharmacogenetics. Therefore, the goal of this exploratory study was to re-examine data from a double-blind placebo controlled laboratory trial of naltrexone for pharmacogenetic effects at kappa and delta opioid receptor tag SNPs. Participants were 40 heavy drinkers (12 female) who underwent an intravenous alcohol challenge paradigm after receiving naltrexone (50mg) or placebo in randomized and crossover fashion. Dependent variables were self-reported alcohol-induced stimulation, sedation, and craving. Multilevel models revealed a significant Naltrexone×OPRK1 Genotype (rs997917) interaction predicting alcohol-induced sedation, such that TT homozygotes reported lower naltrexone-induced alcohol sedation as compared to carriers of the C allele. Moreover, there was a significant Naltrexone×OPRD1 Genotype (rs4654327) interaction predicting alcohol-induced stimulation and craving, such that carriers of the A allele at this locus reported greater naltrexone-induced blunting of alcohol stimulation and alcohol craving compared to GG homozygotes. These findings suggest that additional pharmacogenetic effects in the opioid receptor system may account for individual differences in response to naltrexone in the human laboratory.

A118G Mu Opioid Receptor polymorphism increases inhibitory effects on CaV2.2 channels

Single nucleotide polymorphisms (SNPs) in the human OPRM1 gene result in common variants of Mu Opioid Receptors (hMORs). The A118G SNP occurs at high frequency in certain human populations and produces an aminoacidic substitution: N40D (hMOR-N to hMOR-D) at protein level. N40D is reported to alter pain thresholds and morphine efficacy. hMORs inhibit CaV2.2 channels (N-type currents) at presynaptic nociceptor terminals in dorsal horn, thus reducing calcium influx, transmitter release, and transmission of noxious signals. Nociceptors express different splice isoforms of CaV2.2. Isoforms distinguished by the presence of alternatively spliced exon e37a are of interest because channels containing e37a are particularly enriched in nociceptors. Recent studies showed that CaV2.2e37a is more sensitive to inhibition by Mu Opioid Receptors than the ubiquitous splice variant CaV2.2e37b. Here, we evaluate the effect of hMOR-N and hMOR-D on cloned CaV2.2e37a channels expressed in mammalian cells. We observe that hMOR-D inhibits CaV2.2e37a currents at agonist concentrations 4-fold lower than those needed to inhibit CaV2.2e37a currents by the same degree via hMOR-N. We observe little difference in hMOR-D and hMOR-N inhibition of CaV2.2e37b currents. Our study demonstrates that this common site of OPRM1 polymorphism affects the inhibitory actions of MORs on both major CaV2.2 isoforms expressed in nociceptors.

A118G mu opioid receptor polymorphism among drug addicts in Malaysia

Drug addiction is an important social problem in many countries. Genetic and environmental factors contribute to the predisposition of drug addiction. Genetic variations at the μ opioid receptor (OPRM1) gene locus have been associated with opiate addiction. The present study aims to delineate the frequency of A118G allele of OPRM1 among Malaysian subjects. The frequency of A allele and G allele were 51% and 49%, respectively for addicts and about 73% and 27% respectively for healthy volunteers. The frequency of G allele was 1.77-fold higher in addicts by odds ratio calculation at 95% Cl, which indicate the G allele to be strongly associated with addiction X(2) = 15.31,P < 0.0001; odds ratio 2.51; 95% Cl (1.575-3.994), compared to healthy volunteers. A significant association was observed between A118G polymorphism in μ opioid receptor gene and drug addiction.

Pharmacological Consequence of the A118G μ Opioid Receptor Polymorphism on Morphine- and Fentanyl-mediated Modulation of Ca2+Channels in Humanized Mouse Sensory Neurons

The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele. The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele. The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice. This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.

Gene and gene by sex associations with initial sensitivity to nicotine in nonsmokers

Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 microg/kg) was administered through nasal spray followed by mood, nicotine reward (e.g. 'liking') and perception (e.g. 'feel effects') measures, physiological responses, sensory processing (prepulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine versus placebo spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of tandem repeats (VNTR)], presence of the 7-repeat allele was associated with greater aversive responses to nicotine (decreases in 'vigor', positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased 'feel effects' and greater startle response, but in men only. Other genetic associations were also observed in men but not women, such as greater 'feel effects' and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism (mu opioid receptor polymorphism 1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine before the onset of dependence and may do so differentially between men and women.

The pharmacogenetics of analgesia

Genomic variations influencing response to pharmacotherapy of pain are under investigation. Candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy are discussed. Drug metabolising enzymes represent a further major target of ongoing research in order to identify associations between an individual's genetic profile and drug response (pharmacogenetics). Polymorphisms of the cytochrome P450 enzymes influence analgesic efficacy of codeine, tramadol and tricyclic antidepressants (CYP2D6). Blood levels of some NSAIDs are dependent on CYP2C9 activity, whereas opioid-receptor polymorphisms are discussed for differences in opioid mediated analgesia and side effects. Pharmacogenetics as a diagnostic tool has the potential to improve patient therapy and care, and it is hoped that pharmacogenetics will individualise drug treatment to a greater extent in the near future.

A118G POLYMORPHISM IN MU OPIOID RECEPTOR GENE (OPRM1): ASSOCIATION WITH OPIATE ADDICTION IN SUBJECTS OF INDIAN ORIGIN

The opioidergic hypothesis suggests an association between genetic variations at the opioid receptor mu 1 (OPRM1) gene locus and opiate addiction. The OPRM1 gene, which encodes for mu opioid receptor, contains several single nucleotide polymorphisms (SNPs) in exon I. Two of these, C17T and A118G, have been reported to be associated with substance abuse. The present study aims to delineate the frequency of these variants in the subjects of Indian origin and study their association with the phenotype of opioid dependence. A118G (rs 1799971) and C17T (rs 1799972) were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. For 118G allele, the control subjects (n = 156) showed a frequency of 0.12 while the opioid dependents (n = 126) had an approximately 2.5-fold higher frequency of 0.31 (Odds Ratio 3.501; CI(95%) 2.212-5.555; p < 0.0001). For C17T polymorphism, the controls (n = 57) showed a frequency of 0.89 for C allele versus 0.83 seen in dependents (n = 123; odds ratio of 0.555; CI(95%) 0.264-1.147; p = 0.121). A significant association was observed between the 118G allele and no association was seen with C17T polymorphism and opioid dependence.

The pharmacogenetics of analgesia

Genomic variations influencing response to pharmacotherapy of pain are under investigation. Candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy are discussed. Drug metabolising enzymes represent a further major target of ongoing research in order to identify associations between an individual's genetic profile and drug response (pharmacogenetics). Polymorphisms of the cytochrome P450 enzymes influence analgesic efficacy of codeine, tramadol and tricyclic antidepressants (CYP2D6). Blood levels of some NSAIDs are dependent on CYP2C9 activity, whereas opioid-receptor polymorphisms are discussed for differences in opioid mediated analgesia and side effects. Pharmacogenetics as a diagnostic tool has the potential to improve patient therapy and care, and it is hoped that pharmacogenetics will individualise drug treatment to a greater extent in the near future.

Individualizing analgesic prescription Part I: pharmacogenetics of opioid analgesics.

The current use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic processes, and each of these components, in addition to pain perception and processing, seem to be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After usual dose, drug toxicity, as well as inefficacy, can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. Thus, cytochrome P450 (CYP)2D6 polymorphism influences codeine and tramadol analgesic effects, CYP2C9 has an impact on the disposition of some nonsteroidal anti-inflammatory drugs, and opioid receptor polymorphism (118A>G) may reduce morphine potency. Moreover, drug interaction mimics genetic deficiency and contributes to the variability in response to analgesics. This two-part review summarizes the available data on the pharmacokinetic-pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes (CYP and uridine diphosphate glucuronosyltransferase), drug transporters (multidrug resistance proteins, multidrug resistance-associated proteins, organic anion-transporting polypeptides, and serotonin transporters), relevant drug targets (such as µ-opioid receptor, serotonin receptor and cyclooxygenases) and other nonopioid biological systems, on currently prescribed central and peripheral analgesics.

Genetik, Schmerz und Analgesie

Genomic variations influencing nociceptive sensitivity and susceptibility to pain conditions, as well as responses to pharmacotherapy of pain are currently under investigation. Candidate genes involved in pain perception, pain processing and pain management such as (opioid) receptors, transporters and other targets of pharmacotherapy are discussed. Drug metabolizing enzymes represent a further major target of ongoing research in order to identify associations between an individual's genetic profile and drug response (pharmacogenetics). Polymorphisms of the cytochrome P 450 enzymes influence analgesic efficacy of codeine, tramadol and tricyclic antidepressants (CYP2D6). Blood levels of some non-steroidal anti-inflammatory drugs (NSAIDs) are dependent on CYP2C9 activity, whereas opioid receptor polymorphisms are discussed with respect to differences in opioid-mediated analgesia and side-effects. Pharmacogenetics is seen as a potential diagnostic tool for improving patient therapy and care and will contribute to a more individualized drug treatment in the future.

Genotype and smoking history affect risk of levodopa-induced dyskinesias in Parkinson's disease

Parkinson's disease (PD) patients vary widely in their response to levodopa treatment, and this variation may be partially genetic in origin. We determined whether particular dopamine and opioid receptor polymorphisms were associated with risk of earlier onset of dyskinesia side effects during levodopa therapy. Smoking status was also examined. The 92 subjects were recruited from the movement disorders clinic of a neurology practice associated with a medical school. All were adult-onset PD patients who had been taking levodopa at least 5 years and/or had developed levodopa-induced dyskinesia. Carrying the G-allele of the A118G single nucleotide coding region polymorphism of the mu opioid receptor, as well as a history of never smoking, were independently associated with increased risk of earlier onset of dyskinesia (P=0.05 and 0.02, respectively). One genotype of the D2 dopamine receptor intronic dinucleotide repeat polymorphism (14 repeats/15 repeats, with frequency of 6%) was also associated with earlier dyskinesia (P=0.003). History of smoking has previously been associated with reduced risk of developing PD. Our results suggest that smoking history may also influence the response to levodopa, with contribution comparable to those of individual genes including the mu opioid receptor and D2 dopamine receptor.