Original Report| Volume 15, ISSUE 8, P878-885, August 2014

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Correlation Between Ventral Striatal Catecholamine Content and Nociceptive Thresholds in Neuropathic Mice

  • Anna M.W. Taylor
    Department of Anesthesiology and Perioperative Medicine, University of California, Irvine, California

    Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California
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  • Niall P. Murphy
    Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California
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  • Christopher J. Evans
    Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California
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  • Catherine M. Cahill
    Address reprint requests to Catherine M. Cahill, PhD, Department of Anesthesiology and Perioperative Medicine, University of California, 2117 Gillespie Neuroscience Research Facility, 837 Health Sciences Rd, Irvine, CA 92697.
    Department of Anesthesiology and Perioperative Medicine, University of California, Irvine, California
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      • Neuropathic pain resulted in loss dopamine and rise in norepinephrine content in the ventral striatum.
      • Pain thresholds no longer correlated with ventral striatal dopamine content in neuropathic pain.
      • Ventral striatal norepinephrine content correlated with pain thresholds only in neuropathic pain.
      • These results point to a dramatic change in striatal catecholamine signaling in neuropathic pain.


      Neuropathic pain is characterized by persistent, intractable pain following damage or dysfunction of the nervous system. Analgesics that include central, rather than purely peripheral, targets are more effective when treating neuropathic pain, highlighting the spinal and/or supraspinal mechanisms that contribute to this aberrant pain condition. The striatum represents one of the brain regions that have been implicated in pain processing. Release of dopamine in the ventral striatum is normally associated with analgesia. Clinical and human imaging studies suggest that dopamine is disrupted in neuropathic pain patients, although the conclusions drawn from these studies are limited by their noninvasive imaging or pharmacologic approaches. In this study, we used a C57Bl/6 mouse model of neuropathic pain to describe the changes in neurotransmitter content in the striatum and their relationship to evoked pain thresholds. Striatal dopamine content negatively correlated with mechanical thresholds in sham animals. Neuropathic pain animals had reduced dopamine content that was not correlated with mechanical thresholds. In contrast, norepinephrine content was significantly increased and correlated with mechanical thresholds in neuropathic, but not sham, animals. These results describe changes in striatal signaling in neuropathic pain animals and contribute to the literature defining the role of dopamine and norepinephrine in mediating sensory thresholds in healthy and neuropathic pain states.


      Results show significant loss of ventral striatal dopamine in neuropathic pain conditions, and the relationship of ventral striatal catecholamines to pain thresholds is changed in neuropathic pain. These results complement human imaging studies and provide evidence that chronic pain alters the function of reward systems.

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        • Arbuthnott G.W.
        • Fairbrother I.S.
        • Butcher S.P.
        Dopamine release and metabolism in the rat striatum: An analysis by “in vivo” brain microdialysis.
        Pharmacol Ther. 1990; 48: 281-293
        • Aston-Jones G.
        • Cohen J.D.
        An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance.
        Annu Rev Neurosci. 2005; 28: 403-450
        • Berridge C.W.
        • Waterhouse B.D.
        The locus coeruleus-noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes.
        Brain Res Brain Res Rev. 2003; 42: 33-84
        • Berridge K.C.
        • Robinson T.E.
        What is the role of dopamine in reward: Hedonic impact, reward learning, or incentive salience?.
        Brain Res Brain Res Rev. 1998; 28: 309-369
        • Chaplan S.R.
        • Bach F.W.
        • Pogrel J.W.
        • Chung J.M.
        • Yaksh T.L.
        Quantitative assessment of tactile allodynia in the rat paw.
        J Neurosci Methods. 1994; 53: 55-63
        • Clifford T.J.
        • Warsi M.J.
        • Burnett C.A.
        • Lamey P.J.
        Burning mouth in Parkinson's disease sufferers.
        Gerodontology. 1998; 15: 73-78
        • Daw N.D.
        • Kakade S.
        • Dayan P.
        Opponent interactions between serotonin and dopamine.
        Neural Netw. 2002; 15: 603-616
        • Dayan P.
        • Huys Q.J.
        Serotonin, inhibition, and negative mood.
        PLoS Comput Biol. 2008; 4: e4
        • Deakin J.F.
        • Graeff F.G.
        5-HT and mechanisms of defence.
        J Psychopharmacol. 1991; 5: 305-315
        • Fletcher P.J.
        Dopamine receptor blockade in nucleus accumbens or caudate nucleus differentially affects feeding induced by 8-OH-DPAT injected into dorsal or median raphe.
        Brain Res. 1991; 552: 181-189
        • Fletcher P.J.
        Injection of 5-HT into the nucleus accumbens reduces the effects of d-amphetamine on responding for conditioned reward.
        Psychopharmacology. 1996; 126: 62-69
        • Ford B.
        Pain in Parkinson's disease.
        Clin Neurosci. 1998; 5: 63-72
        • Gerdelat-Mas A.
        • Simonetta-Moreau M.
        • Thalamas C.
        • Ory-Magne F.
        • Slaoui T.
        • Rascol O.
        • Brefel-Courbon C.
        Levodopa raises objective pain threshold in Parkinson's disease: A RIII reflex study.
        J Neurol Neurosurg Psychiatry. 2007; 78: 1140-1142
        • Goetz C.G.
        • Tanner C.M.
        • Levy M.
        • Wilson R.S.
        • Garron D.C.
        Pain in Parkinson's disease.
        Mov Disord. 1986; 1: 45-49
        • Hagelberg N.
        • Forssell H.
        • Aalto S.
        • Rinne J.O.
        • Scheinin H.
        • Taiminen T.
        • Nagren K.
        • Eskola O.
        • Jaaskelainen S.K.
        Altered dopamine D2 receptor binding in atypical facial pain.
        Pain. 2003; 106: 43-48
        • Hagelberg N.
        • Forssell H.
        • Rinne J.O.
        • Scheinin H.
        • Taiminen T.
        • Aalto S.
        • Luutonen S.
        • Nagren K.
        • Jaaskelainen S.
        Striatal dopamine D1 and D2 receptors in burning mouth syndrome.
        Pain. 2003; 101: 149-154
        • Hagelberg N.
        • Jaaskelainen S.K.
        • Martikainen I.K.
        • Mansikka H.
        • Forssell H.
        • Scheinin H.
        • Hietala J.
        • Pertovaara A.
        Striatal dopamine D2 receptors in modulation of pain in humans: A review.
        Eur J Pharmacol. 2004; 500: 187-192
        • Jaaskelainen S.K.
        • Rinne J.O.
        • Forssell H.
        • Tenovuo O.
        • Kaasinen V.
        • Sonninen P.
        • Bergman J.
        Role of the dopaminergic system in chronic pain—A fluorodopa-PET study.
        Pain. 2001; 90: 257-260
        • Kapur S.
        • Remington G.
        Serotonin-dopamine interaction and its relevance to schizophrenia.
        Am J Psychiatry. 1996; 153: 466-476
        • Mosconi T.
        • Kruger L.
        Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: Ultrastructural morphometric analysis of axonal alterations.
        Pain. 1996; 64: 37-57
        • Oe T.
        • Tsukamoto M.
        • Nagakura Y.
        Reserpine causes biphasic nociceptive sensitivity alteration in conjunction with brain biogenic amine tones in rats.
        Neuroscience. 2010; 169: 1860-1871
        • Ozaki S.
        • Narita M.
        • Narita M.
        • Iino M.
        • Sugita J.
        • Matsumura Y.
        • Suzuki T.
        Suppression of the morphine-induced rewarding effect in the rat with neuropathic pain: Implication of the reduction in mu-opioid receptor functions in the ventral tegmental area.
        J Neurochem. 2002; 82: 1192-1198
        • Saade N.E.
        • Atweh S.F.
        • Bahuth N.B.
        • Jabbur S.J.
        Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons.
        Brain Res. 1997; 751: 1-12
        • Sandyk R.
        • Bamford C.R.
        • Iacono R.P.
        Pain and sensory symptoms in Parkinson's disease.
        Int J Neurosci. 1988; 39: 15-25
        • Semenchuk M.R.
        • Sherman S.
        • Davis B.
        Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain.
        Neurology. 2001; 57: 1583-1588
        • Smith H.S.
        Opioids and neuropathic pain.
        Pain Physician. 2012; 15: ES93-ES110
        • Snider S.R.
        • Fahn S.
        • Isgreen W.P.
        • Cote L.J.
        Primary sensory symptoms in parkinsonism.
        Neurology. 1976; 26: 423-429
        • Sotres-Bayon F.
        • Torres-Lopez E.
        • Lopez-Avila A.
        • del Angel R.
        • Pellicer F.
        Lesion and electrical stimulation of the ventral tegmental area modify persistent nociceptive behavior in the rat.
        Brain Res. 2001; 898: 342-349
        • Taylor B.K.
        • Joshi C.
        • Uppal H.
        Stimulation of dopamine D2 receptors in the nucleus accumbens inhibits inflammatory pain.
        Brain Res. 2003; 987: 135-143
        • Weitemier A.Z.
        • Murphy N.P.
        Accumbal dopamine and serotonin activity throughout acquisition and expression of place conditioning: Correlative relationships with preference and aversion.
        Eur J Neurosci. 2009; 29: 1015-1026
        • Witjas T.
        • Kaphan E.
        • Azulay J.P.
        • Blin O.
        • Ceccaldi M.
        • Pouget J.
        • Poncet M.
        • Cherif A.A.
        Nonmotor fluctuations in Parkinson's disease: Frequent and disabling.
        Neurology. 2002; 59: 408-413
        • Wood P.B.
        • Patterson 2nd, J.C.
        • Sunderland J.J.
        • Tainter K.H.
        • Glabus M.F.
        • Lilien D.L.
        Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: A pilot study.
        J Pain. 2007; 8: 51-58
        • Wood P.B.
        • Schweinhardt P.
        • Jaeger E.
        • Dagher A.
        • Hakyemez H.
        • Rabiner E.A.
        • Bushnell M.C.
        • Chizh B.A.
        Fibromyalgia patients show an abnormal dopamine response to pain.
        Eur J Neurosci. 2007; 25: 3576-3582