raclopride and Pain

Placebo and nocebo effects, the therapeutic and adverse effects, respectively, of inert substances or sham procedures, represent serious confounds in the evaluation of therapeutic interventions. They are also an example of cognitive processes, particularly expectations, capable of influencing physiology.. To examine the contribution of 2 different neurotransmitters, the endogenous opioid and the dopaminergic (DA) systems, to the development of placebo and nocebo effects.. Using a within-subject design, subjects twice underwent a 20-minute standardized pain challenge, in the absence and presence of a placebo with expected analgesic properties. Studies were conducted in a university hospital setting.. Twenty healthy men and women aged 20 to 30 years recruited by advertisement.. Activation of DA and opioid neurotransmission by a pain stressor with and without placebo (changes in the binding potential of carbon 11 [11C]-labeled raclopride and [11C] carfentanil with positron emission tomography) and ratings of pain, affective state, and anticipation and perception of analgesia.. Placebo-induced activation of opioid neurotransmission was detected in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter. Dopaminergic activation was observed in the ventral basal ganglia, including the nucleus accumbens. Regional DA and opioid activity were associated with the anticipated and subjectively perceived effectiveness of the placebo and reductions in continuous pain ratings. High placebo responses were associated with greater DA and opioid activity in the nucleus accumbens. Nocebo responses were associated with a deactivation of DA and opioid release. Nucleus accumbens DA release accounted for 25% of the variance in placebo analgesic effects.. Placebo and nocebo effects are associated with opposite responses of DA and endogenous opioid neurotransmission in a distributed network of regions. The brain areas involved in these phenomena form part of the circuit typically implicated in reward responses and motivated behavior.

Topics: Adult; Analgesics; Brain; Brain Mapping; Carbon Radioisotopes; Culture; Female; Fentanyl; Humans; Image Processing, Computer-Assisted; Male; Pain; Pain Measurement; Placebo Effect; Positron-Emission Tomography; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Opioid; Receptors, Opioid, mu; Synaptic Transmission

Positron Emission Tomography (PET) with appropriate radiotracers and quantification methods allows the detection of changes in endogenous neurotransmission by determine the reduction in the binding potential (BP) of receptors before and after experimental challenges. These have typically employed psychostimulants and PET with dopamine (DA) receptor radiotracers. However, reductions in BP persist far beyond the increases in the release of the endogenous neurotransmitter, an effect ascribed to receptor internalization and recycling, a possible confound in repeated studies. Here we examined the time-course of changes in BP during a nonpharmacological challenge, moderate levels of sustained pain, shown to induce robust reductions in micro-opioid and DA D2 BP, as measured with [(11)C]carfentanil and [(11)C]raclopride. It was hypothesized that, contrary to pharmacological probes, the use of a more "physiological" stimulus would not be associated with persistent changes in the BP measures. The pain challenge was associated with reductions in micro-opioid receptor BP in several cortical and subcortical regions. These did not persist in a subsequent scan. Similar results were obtained for DA D2 receptor BP, where the pain challenge induced significant reductions in the caudate nucleus. These data demonstrate that changes in receptor BP induced by a nonpharmacological challenge did not persist into subsequent scans. They further suggest differences in the effect of pharmacological and nonpharmacological probes on PET BP measures. These may reflect varying levels of change in receptor affinity, receptor internalization, and recycling depending on the type of challenge employed.

Topics: Adult; Analgesics, Opioid; Binding, Competitive; Brain; Brain Mapping; Carbon Radioisotopes; Dopamine Antagonists; Fentanyl; Humans; Male; Pain; Pain Measurement; Positron-Emission Tomography; Raclopride; Time Factors

Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [(11)C]-raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread pain and discomfort in fibromyalgia and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored.

Topics: Adult; Analysis of Variance; Area Under Curve; Brain Mapping; Carbon Isotopes; Case-Control Studies; Corpus Striatum; Dopamine; Dopamine Antagonists; Female; Fibromyalgia; Humans; Middle Aged; Pain; Pain Measurement; Positron-Emission Tomography; Psychophysics; Raclopride; Saline Solution, Hypertonic

We studied in rats with a spinal nerve ligation-induced neuropathy whether dopamine D2 receptors (D2Rs) play a role in descending control of pain induced by stimulation of the primary motor cortex (M1). Noxious heat-evoked responses were determined in spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons, with and without electrical M1 stimulation. A D2R antagonist, raclopride, was administered into the dorsal striatum or spinally in attempts to reverse spinal antinociception induced by M1 stimulation. Moreover, influence of M1 stimulation on the noxious heat-induced limb withdrawal reflex was determined following block of spinal D2Rs with raclopride or a lidocaine-induced block of the hypothalamic A11 cell group, the main source of spinal dopamine. Striatal administration of raclopride enhanced the heat-evoked baseline responses of WDR but not NS neurons and reversed the M1 stimulation-induced suppression of the heat response in WDR neurons. Following spinal administration of raclopride, M1 stimulation failed to suppress the heat response of WDR neurons, whereas the heat response of NS neurons was enhanced by M1-stimulation. After blocking the A11 with lidocaine or spinal D2Rs with raclopride, M1 stimulation failed to suppress the noxious heat-evoked withdrawal reflex. The results indicate that descending pain control induced by stimulation of the M1 cortex in neuropathic animals involves supraspinal (presumably striatal) and, through A11, spinal D2Rs. Supraspinal and spinal D2Rs have partly dissociative effects on spinal dorsal horn WDR and NS neurons, possibly reflecting differential roles and wirings that these sensory neurons have in pain-processing circuitries.

Topics: Analysis of Variance; Animals; Deep Brain Stimulation; Disease Models, Animal; Dopamine Antagonists; Functional Laterality; Hot Temperature; Indoles; Male; Motor Cortex; Motor Neurons; Nociceptors; Pain; Pain Measurement; Peripheral Nervous System Diseases; Piperidines; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reflex; Spinal Cord

Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation and hormonal and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here, we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [(11)C]raclopride PET at baseline and during a standardized pain stress challenge. Allelic variation in the leptin gene was associated with varying levels of dopamine release in response to the pain stressor, but not with baseline D2/3 receptor availability. Circulating leptin was also positively associated with stress-induced dopamine release. These results show that leptin serves as a regulator of neuronal function in humans and provides an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli as related to metabolic function. The capacity for leptin to influence stress-induced dopaminergic function is of importance for pathological states where dopamine is thought to play an integral role, such as mood, substance-use disorders, eating disorders, and obesity.

Topics: Adult; Alleles; Body Mass Index; Dopamine; Female; Gene Frequency; Genotype; Humans; Image Processing, Computer-Assisted; Leptin; Male; Microarray Analysis; Neostriatum; Nucleus Accumbens; Pain; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Raclopride; Radiopharmaceuticals; Stress, Psychological; Young Adult

The mechanism of the antinociceptive effects of nitrous oxide (N(2)O) has not been completely elucidated. On the other hand, numerous studies have indicated that mesolimbic dopaminergic neurons, which are thought to be involved in rewarding and reinforcement processes, play important roles in the supraspinal pain-suppression system. We hypothesized that the mesolimbic dopaminergic system is involved in the antinociceptive effect of N(2)O.. Adult male Fischer rats were used in this study. To examine whether the dopaminergic system is activated by N(2)O, frozen sections of the ventral tegmental area of rats exposed to 75% N(2)O were double-stained for c-Fos and tyrosine hydroxylase. To clarify whether the dopaminergic system is involved in the antinociceptive action of N(2)O, saline or raclopride, a dopamine D(2)-like receptor antagonist, was injected into the nucleus accumbens (NAc) shell region. After exposure to 25% oxygen-75% nitrogen or 25% oxygen-75% N(2)O for 30 min, rats were subjected to formalin test, and the spinal cord was examined immunohistochemically.. Exposure to 75% N(2)O increased c-Fos expression in tyrosine hydroxylase-positive cells in the ventral tegmental area. Raclopride, injected into the NAc shell region, attenuated the antinociceptive effect of N(2)O in the formalin test, and blocked the suppressive effect of N(2)O on the formalin-induced c-Fos expression in the dorsal horn of the spinal cord by N(2)O.. It is possible that inhalation of N(2)O activates mesolimbic dopaminergic neurons, and that the antinociceptive effect of N(2)O is at least partially mediated by dopamine D(2)-like receptors in the NAc shell region.

Topics: Analgesics; Animals; Behavior, Animal; Disease Models, Animal; Dopamine Antagonists; Formaldehyde; Male; Microinjections; Nitrous Oxide; Nucleus Accumbens; Pain; Pain Measurement; Proto-Oncogene Proteins c-fos; Raclopride; Rats; Rats, Inbred F344; Receptors, Dopamine D2; Time Factors; Tyrosine 3-Monooxygenase; Up-Regulation; Ventral Tegmental Area

The antinociceptive effects of the serotonin (5-HT)1A/7 receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) administered into the medial thalamus were evaluated. Pain behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization after discharges, VADs) levels of the neuraxis were elicited by tailshock. Administration of 8-OH-DPAT (5, 10, and 20 microg/side) into nucleus parafascicularis (nPf) produced dose-dependent increases in VDS and VAD thresholds, but failed to elevate SMR threshold. The increase in VAD threshold was significantly greater than that of VDS threshold. Similar effects were observed with administration of 8-OH-DPAT (20 microg/side) into the rostral portion of the central lateral thalamic nucleus. The bilateral or unilateral administration of 8-OH-DPAT (20 microg) into other thalamic nuclei, or into sites dorsal to nPf, did not elevate vocalization thresholds. Increases in vocalization thresholds produced by nPf-administered 8-OH-DPAT were mediated by both 5-HT1A and 5-HT7 receptors. Intra-nPf administration of the 5-HT1A receptor antagonist WAY-100635 (0.05 or 0.5 microg/side), or the 5-HT7 receptor antagonist SB-269970 (1 or 2 microg/side), but not the dopamine D2 receptor antagonist raclopride (10 microg/side), reversed 8-OH-DPAT induced elevations in vocalization thresholds. These results provide the first reported evidence of behavioral antinociception following the administration of a 5-HT agonist into the medial thalamus.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Affect; Analysis of Variance; Animals; Behavior, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Functional Laterality; Intralaminar Thalamic Nuclei; Male; Medulla Oblongata; Neural Inhibition; Pain; Pain Measurement; Pain Threshold; Phenols; Physical Stimulation; Piperazines; Prosencephalon; Pyridines; Raclopride; Rats; Rats, Long-Evans; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Cord; Sulfonamides; Vocalization, Animal

Striatal dopamine D2/D3 receptors have been suggested to play a role in pain sensitivity and placebo effect. We studied whether the association of dopamine D2/D3 receptor binding potential (BP) with sensory thresholds is specific to the modality of pain, and whether striatal dopamine D2/D3 receptor BP predicts the magnitude of placebo analgesia. Pain and tactile thresholds, and placebo analgesia were assessed in eight healthy human male subjects who had previously participated in a dopamine D2/D3 receptor positron emission tomography study with [11C]raclopride. The results show that the cutaneous heat pain threshold was inversely correlated with dopamine D2/D3 receptor BP in the right putamen, but responses to tactile stimulation did not correlate with striatal dopamine D2/D3 receptor BP. Placebo-induced elevation of the heat pain threshold did not correlate with striatal dopamine D2/D3 receptor BP. These results suggest that the influence of striatal dopamine D2/D3 receptors on sensory thresholds is selective for the modality of pain. Moreover, striatal dopamine D2/D3 receptor BP appears not to predict individual's analgesic response to placebo.

Topics: Adult; Analgesia; Binding, Competitive; Corpus Striatum; Dopamine Antagonists; Functional Laterality; Humans; Hyperalgesia; Male; Pain; Pain Threshold; Physical Stimulation; Placebo Effect; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Sensory Thresholds; Touch

We studied in healthy humans the contribution of cerebral dopamine D2/D3 receptors to individual differences in response characteristics to painful stimulation. Positron emission tomography was used to measure the dopamine D2/D3 binding potential (D2/D3 BP) with [(11)C]raclopride in the striatum (n = 8) and with [(11)C]FLB 457 in the extrastriatal regions (n = 11). Sensitivity to cutaneous heat pain was assessed by a traditional threshold method and by an analysis based on the signal detection theory which allows the separation of an individual subject's discriminative capacity from the response criterion, i.e. the area under the receiver operating characteristic curve provides a measure of the sensory discriminability (sensory factor) and the response criterion gives an estimate of the subject's response bias or attitude (nonsensory factor). The pain threshold and response criterion were inversely correlated with the D2/D3 BP in the right putamen, whereas the discriminative capacity was not significantly correlated with the D2/D3 BP in any brain region. The correlation of the D2/D3 BP in the putamen with the pain threshold and the subject's response criterion may rather be explained by a dopaminergic effect on nonsensory factors determining the subject's attitude towards pain than by a dopaminergic effect on the subject's discriminative capacity. Alternatively, striatal dopamine D2/D3 receptors could control a modulatory pathway producing a parallel shift in the stimulus-response function for sensory signals, mimicking a change in the subject's response criterion.

Topics: Adult; Area Under Curve; Carbon Radioisotopes; Corpus Striatum; Dopamine Antagonists; Humans; Male; Pain; Pain Measurement; Pain Threshold; Positron-Emission Tomography; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; ROC Curve; Salicylamides

The pain modulatory role of dopamine D2 receptors of the human forebrain was studied by determining the association between dopamine D2 receptor binding potential and the response to experimental pain. Nineteen healthy male volunteers participated in a dopamine D2 receptor positron emission tomography study. The extrastriatal regions of interest studied with [11C]FLB 457 as radioligand (n = 11) were the anterior cingulum, the medial and lateral thalamus, the medial and lateral frontal cortex, and the medial and lateral temporal cortex. The striatal regions of interest studied with [11C]raclopride (n = 8) were the caudate nucleus and the putamen. The latency to the ice water-induced cold pain threshold and tolerance were determined in a separate psychophysical test session. Moreover, the cutaneous heat pain threshold and its elevation by concurrent cold pain in the contralateral hand were determined in each subject. Cold pain threshold was inversely correlated with D2 binding potential in the right putamen and the cold pain tolerance was inversely correlated with D2 binding potential in the right medial temporal cortex. The magnitude of heat pain threshold elevation induced by concurrent cold pain was directly correlated with D2 binding potential in the left putamen. Other correlations of D2 binding potentials in varying brain regions with sensory responses were not significant. A psychophysical control study (n = 10) showed that cold pain responses were identical in the right and left hand. The results indicate that dopamine D2 receptor binding potential in the human forebrain, particularly in the striatum, may be an important parameter in determining the individual cold pain response and the potential for central pain modulation. Accordingly, an individual with only few available D2 receptors in the forebrain is likely to have a high tonic level of pain suppression, combined with a low capacity to recruit more (dopaminergic) central pain inhibition by noxious conditioning stimulation.

Topics: Adult; Brain; Carbon Radioisotopes; Cold Temperature; Conditioning, Psychological; Dopamine Antagonists; Humans; Male; Pain; Pain Threshold; Psychophysics; Raclopride; Receptors, Dopamine D2; Tomography, Emission-Computed

Previous research has demonstrated that pharmacological stimulation of postsynaptic dopamine D2 receptors produces increases in serotonin output. The present study explored whether this relationship also holds under physiological conditions. Accordingly, we examined the effects of D2 receptor blockade or unilateral dopamine depletion on behaviorally induced increases in extracellular serotonin levels in the corpus striatum and prefrontal cortex of freely moving rats using in vivo microdialysis. Extracellular levels of dopamine and serotonin, as well as behavioral activity, were increased by both mild tail pinch and the light-dark transition. Tail pinch-induced increases in serotonin levels (39+/-3% and 53+/-5% in the corpus striatum and prefrontal cortex, respectively), but not the accompanying behavioral changes, were blocked by local application of the D2 receptor antagonist raclopride (10 microM). D2 receptor blockade also disrupted the positive relationship between striatal serotonin levels and behavioral activity of animals across the light-dark transition (r=0.93 without raclopride, r=0.24 in presence of raclopride). Unilateral 6-hydroxydopamine lesion of the nigrostriatal dopaminergic system also abolished increases in striatal serotonin output induced by both tail pinch and light-dark transition. A negative correlation was observed between the degree of striatal dopamine depletion and tail pinch-induced increases in serotonin efflux (r= - 0.88). Thus, both a local blockade of postsynaptic D2 receptors and striatal dopamine depletion prevented increases in serotonin output that normally accompany behavioral activation. These data indicate that the increases in the forebrain serotonin output produced by two distinct physiological/environmental manipulations appear to be largely dependent upon intact local dopaminergic neurotransmission.

Topics: Animals; Behavior, Animal; Corpus Striatum; Darkness; Dopamine; Dopamine Antagonists; Light; Male; Microdialysis; Oxidopamine; Pain; Prefrontal Cortex; Prosencephalon; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Salicylamides; Serotonin; Stress, Physiological; Substantia Nigra; Tail

Delta(9)-Tetrahydrocannabinol (1 and 5 mg/kg, i.p.) produced, dose-dependently, antinociceptive effects using hot plate and tail flick tests in rats. These effects were suppressed not only by the cannabinoid CB(1) receptor antagonist SR 141716A (0.5 mg/kg; i.p.) but also by the dopamine D(2) receptor antagonists S(-)-sulpiride (5 and 10 mg/kg; i.p.) and S(-)-raclopride (1.5 and 3 mg/kg; i.p.). Conversely, Delta(9)-tetrahydrocannabinol antinociceptive effects were potentiated by the dopamine D(2) receptor agonists (-)-quinpirole (0.025 mg/kg, s.c.) and (+)-bromocriptine (0.5 and 1 mg/kg; i.p.). Our results indicate that the antinociceptive effects of Delta(9)-tetrahydrocannabinol are mediated by the concomitant activation of cannabinoid CB(1) and dopamine D(2) receptors and that dopamine D(2) receptor agonists may be useful in improving the analgesic effects of cannabinoids.

Topics: Analgesics, Non-Narcotic; Animals; Bromocriptine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dronabinol; Male; Nociceptors; Pain; Piperidines; Pyrazoles; Quinpirole; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Rimonabant; Sulpiride