Stimulation of dopamine D2 receptors in the nucleus accumbens inhibits inflammatory pain

Previous studies suggest that dopamine in the nucleus accumbens links noxious or mesolimbic stimulation with the feedback inhibition of nociception. To test the hypothesis that pharmacological agonism at dopamine receptors in the nucleus accumbens elicits antinociception, we bilaterally microinjected dopamine D1- and D2-receptor subtype selective drugs, and then evaluated behavioral responses to noxious intraplantar formalin. While the D1-selective agonist SKF 38393 was without effect at a dose of 0.5 nmol/side, the D2-selective agonist quinpirole dose-dependently (0.05-5.0 nmol/side, bilateral) inhibited the persistent phase of formalin-induced nociception. This was blocked by pre-administration of a selective D2-dopaminergic antagonist raclopride (0.3 nmol/side, bilateral). Quinpirole did not produce overt behavioral effects and did not change rotarod latency. Our results indicate that quinpirole acts at dopamine D2 receptors in the nucleus accumbens to inhibit persistent nociception at doses that circumvent confounding non-specific motor deficits, namely, sedation and motor coordination.

[1]  S. Iversen,et al.  Psychomotor-activating effects mediated by dopamine D2 and D3 receptors in the nucleus accumbens , 2000, Pharmacology Biochemistry and Behavior.

[2]  Long-chuan Yu,et al.  Involvement of CGRP and CGRP1 receptor in nociception in the nucleus accumbens of rats , 2001, Brain Research.

[3]  Joshua A. Bueller,et al.  μ-Opioid Receptor-Mediated Antinociceptive Responses Differ in Men and Women , 2002, The Journal of Neuroscience.

[4]  W. Zieglgänsberger,et al.  Supraspinal metabolic activity changes in the rat during adjuvant monoarthritis , 1999, Neuroscience.

[5]  M. North,et al.  Naloxone reversal of morphine analgesia but failure to alter reactivity to pain in the formalin test. , 1978, Life sciences.

[6]  H. Groenewegen,et al.  Organization of the efferent projections of the nucleus accumbens to pallidal, hypothalamic, and mesencephalic structures: A tracing and immunohistochemical study in the cat , 1984, The Journal of comparative neurology.

[7]  A. Kelley,et al.  Differential Behavioral Responses to Dopaminergic Stimulation of Nucleus Accumbens Subregions in the Rat , 1997, Pharmacology Biochemistry and Behavior.

[8]  Behavioural topography in the striatum: differential effects of quinpirole and D-amphetamine microinjections. , 1998, European journal of pharmacology.

[9]  J. Stewart,et al.  The role of dopamine in the nucleus accumbens in analgesia. , 1999, Life sciences.

[10]  D. Jackson,et al.  Role of D1 and D2 dopamine receptors in mediating locomotor activity elicited from the nucleus accumbens of rats , 1989, Brain Research.

[11]  A. Basbaum,et al.  The differential contribution of capsaicin-sensitive afferents to behavioral and cardiovascular measures of brief and persistent nociception and to Fos expression in the formalin test , 1997, Brain Research.

[12]  D. Eilam,et al.  Biphasic effect of D-2 agonist quinpirole on locomotion and movements. , 1989, European journal of pharmacology.

[13]  P. Garris,et al.  Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation , 1999, Nature.

[14]  K. Hole,et al.  Lesions of bulbo-spinal serotonergic or noradrenergic pathways reduce nociception as measured by the formalin test. , 1991, Acta physiologica Scandinavica.

[15]  K. Franklin.  Analgesia and the neural substrate of reward , 1989, Neuroscience & Biobehavioral Reviews.

[16]  P. Garris,et al.  Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  J. B. Justice,et al.  Dopamine D1/D2 agonists injected into nucleus accumbens and ventral pallidum differentially affect locomotor activity depending on site , 1999, Neuroscience.

[18]  R. Burstein,et al.  Retrograde labeling of neurons in spinal cord that project directly to nucleus accumbens or the septal nuclei in the rat , 1989, Brain Research.

[19]  B. Uludaǧ,et al.  Use of levodopa to relieve pain from painful symmetrical diabetic polyneuropathy , 1998, Pain.

[20]  D. Blanchard,et al.  Life-span studies of dominance and aggression in established colonies of laboratory rats , 1988, Physiology & Behavior.

[21]  I. Lucki,et al.  Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists andd-amphetamine , 2005, Psychopharmacology.

[22]  F. E. Bloom,et al.  Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal , 2004, Psychopharmacology.

[23]  M. Zarrindast,et al.  Effects of dopaminergic agents on antinociception in formalin test. , 1999, General pharmacology.

[24]  A. Basbaum,et al.  Continuous intravenous infusion of naloxone does not change behavioral, cardiovascular, or inflammatory responses to subcutaneous formalin in the rat , 1997, Pain.

[25]  Long-chuan Yu,et al.  Anti-nociceptive effect of neuropeptide Y in the nucleus accumbens of rats: an involvement of opioid receptors in the effect , 2002, Brain Research.

[26]  K. D. Cliffer,et al.  Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  Joshua A. Bueller,et al.  Regional Mu Opioid Receptor Regulation of Sensory and Affective Dimensions of Pain , 2001, Science.

[28]  Paul Green,et al.  Altered Nucleus Accumbens Circuitry Mediates Pain-Induced Antinociception in Morphine-Tolerant Rats , 2002, The Journal of Neuroscience.

[29]  K. Franklin,et al.  Infusions of 6-hydroxydopamine into the nucleus accumbens abolish the analgesic effect of amphetamine but not of morphine in the formalin test , 1992, Brain Research.

[30]  K. Franklin,et al.  Morphine analgesia in the formalin test: Evidence for forebrain and midbrain sites of action , 1994, Neuroscience.

[31]  H. Breiter,et al.  Reward Circuitry Activation by Noxious Thermal Stimuli , 2001, Neuron.

[32]  J. Stewart,et al.  Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine. , 1998, The Journal of pharmacology and experimental therapeutics.

[33]  B. Schmidt,et al.  Nicotine withdrawal hyperalgesia and opioid-mediated analgesia depend on nicotine receptors in nucleus accumbens , 2001, Neuroscience.

[34]  Rachael L Neve,et al.  CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[35]  R. Layer,et al.  Effects of morphine in the nucleus accumbens on stimulant-induced locomotion , 1991, Pharmacology Biochemistry and Behavior.

[36]  G. Breese,et al.  6-hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding. , 1987, The Journal of pharmacology and experimental therapeutics.

[37]  G. Mogenson,et al.  Differential effects of quinpirole in the nucleus accumbens depending on the initial level of locomotor activity , 1993, Brain Research Bulletin.

[38]  K. Franklin,et al.  Dopamine receptor subtypes and formalin test analgesia , 1991, Pharmacology Biochemistry and Behavior.

[39]  S. Hunskaar,et al.  The formalin test: an evaluation of the method , 1992, Pain.

[40]  M. Peterson,et al.  Persistent cardiovascular and behavioral nociceptive responses to subcutaneous formalin require peripheral nerve input , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[41]  G. Mogenson,et al.  Quinpirole to the accumbens reduces exploratory and amphetamine-elicited locomotion , 1991, Brain Research Bulletin.

[42]  J. Levine,et al.  Pain-Induced Analgesia Mediated by Mesolimbic Reward Circuits , 1999, The Journal of Neuroscience.

[43]  C. van Hartesveldt,et al.  Effects of intracerebral quinpirole on locomotion in rats. , 1992, European journal of pharmacology.

[44]  D. S. Zahm,et al.  Specificity in the projection patterns of accumbal core and shell in the rat , 1991, Neuroscience.

[45]  W. Kostowski,et al.  Interaction between accumbens D1 and D2 receptors regulating rat locomotor activity , 2004, Psychopharmacology.

[46]  J. Magnusson,et al.  Additional evidence for the involvement of the basal ganglia in formalin-induced nociception: the role of the nucleus accumbens , 2002, Brain Research.

[47]  Wang Ry,et al.  Electrophysiological evidence for the existence of both D-1 and D-2 dopamine receptors in the rat nucleus accumbens , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[48]  S. Kernbaum,et al.  Administration of levodopa for relief of herpes zoster pain. , 1981, JAMA.

[49]  P. Piazza,et al.  Higher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study , 1993, Brain Research.

[50]  L. Kocher.  Systemic naloxone does not affect pain-related behaviour in the formalin test in rat , 1988, Physiology & Behavior.