The aims of this study were to assess the effects of the dopamine agonist apomorphine on experimental pain models in healthy subjects and to explore the possible association between these effects and a common polymorphism within the dopamine transporter gene. Healthy volunteers (n = 105) participated in this randomized double-blind, placebo-controlled, cross-over trial. Heat pain threshold and intensity, cold pain threshold, and the response to tonic cold pain (latency, intensity, and tolerance) were evaluated before and for up to 120 min after the administration of 1.5 mg apomorphine/placebo. A polymorphism (3′-UTR 40-bp VNTR) within the dopamine transporter gene (SLC6A3) was investigated. Apomorphine had an effect only on tolerance to cold pain, which consisted of an initial decrease and a subsequent increase in tolerance. An association was found between the enhancing effect of apomorphine on pain tolerance (120 min after its administration) and the DAT-1 polymorphism. Subjects with two copies of the 10-allele demonstrated significantly greater tolerance prolongation than the 9-allele homozygote carriers and the heterozygote carriers (p = 0.007 and p = 0.003 in comparison to the placebo, respectively). In conclusion, apomorphine administration produced a decrease followed by a genetically associated increase in cold pain tolerance.
References
[1]
Wood PB (2008) Role of central dopamine in pain and analgesia. Expert Rev 8: 781–97.
[2]
Lee MA, Walker RW, Hildreth TJ, Prentice WM (2006) A survey of pain in idiopathic Parkinson's disease. J Pain Symptom Manage 32: 462–9.
[3]
Cervenka S, P？lhagen SE, Comley RA, Panagiotidis G, Cselényi Z, et al. (2006) Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding. Brain 129(Pt 8): 2017–28.
[4]
J？？skel？inen SK, Rinne JO, Forssell H, Tenovuo O, Kaasinen V, et al. (2001) Role of the dopaminergic system in chronic pain a fluorodopa-PET study. Pain 90: 257–60.
[5]
Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, et al. (2007) Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci 25: 3576–82.
[6]
Treister R, Pud D, Ebstein RP, Laiba E, Gershon E, et al. (2009) Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans. Pain 147(1–3): 187–93.
[7]
Karling P, Danielsson ？, Wikgren M, S？derstr？m I, Del-Favero J, et al. (2011) The relationship between the val158met catechol-O-methyltransferase (COMT) polymorphism and irritable bowel syndrome. PLoS One 6(3): e18035.
[8]
Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, et al. (2003) COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299: 1240–3.
[9]
Buskila D, Cohen H, Neumann L, Ebstein RP (2004) An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits. Mol Psychiatry 9(8): 730–1.
[10]
Cevoli S, Mochi M, Scapoli C, Marzocchi N, Pierangeli G, et al. (2006) A genetic association study of dopamine metabolism-related genes and chronic headache with drug abuse. Eur J Neurol 13(9): 1009–13.
[11]
Kim H, Lee H, Rowan J, Brahim J, Dionne RA (2006) Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans. Mol Pain 2: 24.
[12]
Potvin S, Grignon S, Marchand S (2009) Human evidence of a supra-spinal modulating role of dopamine on pain perception. Synapse 63(5): 390–402.
[13]
Ribari？ S (2012) The pharmacological properties and therapeutic use of apomorphine. Molecules 17(5): 5289–309.
[14]
Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, et al. (1992) Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 14: 1104–6.
[15]
Vandenbergh DJ, Persico AM, Uhl GR (1992) A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs. Mol Brain Res 15: 161–6.
[16]
Dickey RP, Minton JP (1981) Levodopa relief of bone pain from breast cancer. N Engl J Med 286(15): 843.
[17]
Ertas M, Sagduyu A, Arac N, Uludag B, Ertekin C (1998) Use of levodopa to relieve pain from painful symmetrical diabetic polyneuropathy. Pain 75: 257–9.
[18]
Holman AJ, Myers RR (2005) A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum 52: 2495–505.
[19]
Hornyak M, Trenkwalder C, Kohnen R, Scholz H (2012) Efficacy and safety of dopamine agonists in restless legs syndrome. Sleep Med 13(3): 228–36.
[20]
Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, et al. (2011) Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev (3): CD006009.
Dellapina E, Gerdelat-Mas A, Ory-Magne F, Pourcel L, Galitzky M, et al. (2011) Apomorphine effect on pain threshold in Parkinson's disease: a clinical and positron emission tomography study. Mov Disord 26(1): 153–7.
[23]
Harris G, Rollman GB (1983) The validity of experimental pain measures. Pain 17: 369–76.
[24]
Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68(5): 815–34.
[25]
Cools R (2008) Role of dopamine in the motivational and cognitive control of behavior. Neuroscientist 14(4): 381–95.
[26]
Salamone JD (1996) The behavioral neurochemistry of motivation: methodological and conceptual issues in studies of the dynamic activity of nucleus accumbens dopamine. J Neurosci Methods 64(2): 137–49.
[27]
Salamone JD, Correa M, Farrar A, Mingote SM (2007) Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacology (Berl) 191(3): 461–82.
[28]
Cools R, D'Esposito M (2011) Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry 69(12): e113–25.
[29]
Hjorth S, Engel JA, Carlsson A (1986) Anticonflict effects of low doses of the dopamine agonist apomorphine in the rat. Pharmacol Biochem Behav 24(2): 237–40.
[30]
Paalzow GH (1992) L-dopa induces opposing effects on pain in intact rats: (-)-sulpiride, SCH 23390 or alpha-methyl-DL-p-tyrosine methylester hydrochloride reveals profound hyperalgesia in large antinociceptive doses. J Pharmacol Exp Ther 263(2): 470–9.
[31]
Floresco SB, West AR, Ash B, Moore H, Grace AA (2003) Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci 6(9): 968–73.
[32]
Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41(1): 1–24.
[33]
Leknes S, Tracey I (2008) A common neurobiology for pain and pleasure. Nat Rev Neurosci 9(4): 314–20.
[34]
de La Fuente-Fernández R, Lim AS, Sossi V, Holden JE, Calne DB, et al. (2001) Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition. J Cereb Blood Flow Metab 21(10): 1151–9.
[35]
Przedborski S, Levivier M, Raftopoulos C, Naini AB, Hildebrand J (1995) Peripheral and central pharmacokinetics of apomorphine and its effect on dopamine metabolism in humans. Mov Disord 10(1): 28–36.
[36]
Dang YH, Xing B, Zhao Y, Zhao XJ, Huo FQ, et al. (2011) The role of dopamine receptors in ventrolateral orbital cortex-evoked antinociception in a rat formalin test model. Eur J Pharmacol 657(1–3): 97–103.
[37]
Meyer PJ, Morgan MM, Kozell LB, Ingram SL (2009) Contribution of dopamine receptors to periaqueductal gray-mediated antinociception. Psychopharmacology (Berl) 204(3): 531–40.
[38]
Fuke S, Suo S, Takahashi N, Koike H, Sasagawa N, et al. (2001) The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression. Pharmacogenomics J 1: 152–6.
[39]
Costa A, Riedel M, Müller U, M？ller HJ, Ettinger U (2011) Relationship between SLC6A3 genotype and striatal dopamine transporter availability: a meta-analysis of human single photon emission computed tomography studies. Synapse 65(10): 998–1005.
[40]
Van Dyck CH, Malison RT, Jacobsen LK, Seibyl JP, Staley JK, et al. (2005) Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. J Nucl Med 46(5): 745–51.
[41]
Haddley K, Vasiliou AS, Ali FR, Paredes UM, Bubb VJ, et al. (2008) Molecular genetics of monoamine transporters: relevance to brain disorders. Neurochem Res 33(4): 652–67.
[42]
Heinz A, Goldman D, Jones DW, Palmour R, Hommer D, et al. (2000) Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 22: 133–139.
[43]
Rokem A, Landau AN, Prinzmetal W, Wallace DL, Silver MA, et al. (2012) Modulation of Inhibition of Return by the Dopamine D2 Receptor Agonist Bromocriptine Depends on Individual DAT1 Genotype. Cereb Cortex 22(5): 1133–8.
[44]
Weickert TW, Goldberg TE, Mishara A, Apud JA, Kolachana BS, et al. (2004) Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry 56(9): 677–82.
[45]
Charbit AR, Akerman S, Goadsby PJ (2009) Comparison of the effects of central and peripheral dopamine receptor activation on evoked firing in the trigeminocervical complex. J Pharmacol Exp Ther 331(2): 752–63.
[46]
Main DC, Waterman AE, Kilpatrick IC, Jones A (1997) An assessment of the peripheral antinociceptive potential of remoxipride, clonidine and fentanyl in sheep using the forelimb tourniquet. J Vet Pharmacol Ther 20(3): 220–8.
