Correlation of human cold pressor pain responses with 5-HT1A receptor binding in the brain

We determined whether serotonin 5-HT(1A) receptor availability in the brain is associated with cold pressor pain (CPP) or sympathetic reflex responses. Psychophysical testing was performed in eleven healthy males who had participated in a positron emission tomography study with [carbonyl-(11)C]WAY-100635 ligand for the assessment of 5-HT(1A) receptor binding potential (BP). Psychophysical testing consisted of determining CPP threshold, tolerance, intensity, unpleasantness and CPP threshold modulation by conditioning CPP. Autonomic control was assessed by determining the cutaneous vasoconstriction responses in the finger induced by CPP and Valsalva maneuver. CPP intensity was inversely correlated with 5-HT(1A) BP in multiple cortical and subcortical areas, including the prefrontal and cingulate cortices, insula, amygdala and the dorsal raphe. CPP unpleasantness was not significantly correlated with 5-HT(1A) BP in any of the regions of interest. Increase of CPP threshold by conditioning CPP was directly correlated with 5-HT(1A) BP in the amygdala and medial prefrontal cortex. Vasoconstriction induced by Valsalva but not CPP was directly correlated with 5-HT(1A) BP in the ventral part of the anterior cingulate cortex and the anterior insula. The results suggest that 5-HT(1A) receptors in the brain influence pain and Valsalva-induced sympathetic vasoconstriction reflex. In general, subjects with high availability of 5-HT(1A) receptors have low CPP intensity accompanied by a high capacity for central suppression of pain or a sympathetic vasoconstriction response by a Valsalva maneuver.

[1]  A. Ramage,et al.  Influence of 5‐HT1A Receptor Agonists on Sympathetic and Parasympathetic Nerve Activity , 1990, Journal of cardiovascular pharmacology.

[2]  Oberg Pa,et al.  Laser-Doppler flowmetry. , 1990 .

[3]  J. Micó,et al.  The role of 5-HT1A receptors in research strategy for extensive pain treatment. , 2006, Current topics in medicinal chemistry.

[4]  J. Hornung,et al.  The human raphe nuclei and the serotonergic system , 2003, Journal of Chemical Neuroanatomy.

[5]  B. Wallin,et al.  Neural control of human skin blood flow. , 1990, Journal of the autonomic nervous system.

[6]  M. Minchin,et al.  Characterisation of the Binding of [3H]WAY‐100635, a Novel 5‐Hydroxytryptamine1A Receptor Antagonist, to Rat Brain , 1995, Journal of neurochemistry.

[7]  B. Vogt.  Pain and emotion interactions in subregions of the cingulate gyrus , 2005, Nature Reviews Neuroscience.

[8]  N. El-Yassir,et al.  A 5-HT1-type receptor mediates the antinociceptive effect of nucleus raphe magnus stimulation in the rat , 1990, Brain Research.

[9]  Victoria Arango,et al.  Regional Heterogeneity of 5-HT1A Receptors in Human Cerebellum as Assessed by Positron Emission Tomography , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  M. Carli,et al.  The 5-HT1A receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT1A receptors , 2000, Psychopharmacology.

[11]  A. Apkarian,et al.  Representation of pain in the brain , 2006 .

[12]  F. Colpaert.  5-HT(1A) receptor activation: new molecular and neuroadaptive mechanisms of pain relief. , 2006, Current opinion in investigational drugs.

[13]  Sean P David,et al.  A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1A Receptor Binding in Humans , 2005, The Journal of Neuroscience.

[14]  J. Tack,et al.  A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome , 2005, Gut.

[15]  Tipu Z. Aziz,et al.  Stimulating the human midbrain to reveal the link between pain and blood pressure , 2006, Pain.

[16]  A. Pertovaara,et al.  5-HT(1A) receptors in endogenous regulation of neuropathic hypersensitivity in the rat. , 2006, European journal of pharmacology.

[17]  Karl J. Friston,et al.  Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems , 2005, The European journal of neuroscience.

[18]  Ralph Myers,et al.  Assessment of Spatial Normalization of PET Ligand Images Using Ligand-Specific Templates , 1999, NeuroImage.

[19]  R. Malekzadeh,et al.  The effect of fluoxetine in patients with pain and constipation‐predominant irritable bowel syndrome: a double‐blind randomized‐controlled study , 2005, Alimentary pharmacology & therapeutics.

[20]  K. Någren,et al.  Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity , 2002, PAIN.

[21]  J. Lance,et al.  Plasma serotonin in patients with chronic tension headaches. , 1989, Journal of neurology, neurosurgery, and psychiatry.

[22]  M. Bushnell,et al.  A psychophysical comparison of sensory and affective responses to four modalities of experimental pain. , 1992, Somatosensory & motor research.

[23]  A. Rissanen,et al.  Brain serotonin 1A receptor binding in bulimia nervosa , 2004, Biological Psychiatry.

[24]  I A Cliffe,et al.  A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. , 1995, European journal of pharmacology.

[25]  W. Riedel,et al.  Acute tryptophan depletion affects brain-gut responses in irritable bowel syndrome patients and controls , 2004, Gut.

[26]  P. U. Rani,et al.  An Evaluation of Antidepressants in Rheumatic Pain Conditions , 1996, Anesthesia and analgesia.

[27]  Q. Lin,et al.  Antinociception and inhibition from the periaqueductal gray are mediated in part by spinal 5-hydroxytryptamine(1A) receptors. , 1996, The Journal of pharmacology and experimental therapeutics.

[28]  M. Rowbotham,et al.  Treatment response in antidepressant-naïve postherpetic neuralgia patients: double-blind, randomized trial. , 2005, The journal of pain : official journal of the American Pain Society.

[29]  S. McMahon,et al.  Wall and Melzack's textbook of pain , 2006 .

[30]  A. Eschalier,et al.  Serotonin and Experimental Pain in Healthy Young Volunteers , 2003, The Clinical journal of pain.

[31]  J. Kajander,et al.  Brain Serotonin 1A Receptor Binding in Bulimia , 2004 .

[32]  M Slifstein,et al.  Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers. , 2001, Nuclear medicine and biology.

[33]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[34]  Qing-ping Wang,et al.  The dorsal raphe: An important nucleus in pain modulation , 1994, Brain Research Bulletin.

[35]  E. Azmitia,et al.  An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat , 1978, The Journal of comparative neurology.

[36]  K. Brøsen,et al.  The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms , 1990, Pain.

[37]  D. Wright,et al.  Comparative localization of serotonin1A, 1C, and 2 receptor subtype mRNAs in rat brain , 1995, The Journal of comparative neurology.

[38]  A. Pizzimenti,et al.  Randomized double‐blind comparison of serotonergic (Citalopram) versus noradrenergic (Reboxetine) reuptake inhibitors in outpatients with somatoform, DSM‐IV‐TR pain disorder , 2005, European journal of pain.

[39]  J. Tack,et al.  Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double‐blind, placebo‐controlled study , 2006, Alimentary pharmacology & therapeutics.

[40]  A. Pertovaara,et al.  Spatial integration of cold pressor pain sensation in humans , 2004, Neuroscience Letters.

[41]  Ramin V. Parsey,et al.  Altered Serotonin 1A Binding in Major Depression: A [carbonyl-C-11]WAY100635 Positron Emission Tomography Study , 2006, Biological Psychiatry.

[42]  Victoria Arango,et al.  Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635 , 2002, Brain Research.

[43]  N. Schneiderman,et al.  Blood pressure reactivity and perception of pain during the forehead cold pressor test. , 1991, Psychophysiology.

[44]  M Slifstein,et al.  Validation and Reproducibility of Measurement of 5-HT1A Receptor Parameters with [carbonyl-11C]WAY-100635 in Humans: Comparison of Arterial and Reference Tissue Input Functions , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[45]  F. Wolfe,et al.  Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. , 1997, The Journal of rheumatology.

[46]  P. Keck,et al.  A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. , 2002, The American journal of medicine.

[47]  Roger N. Gunn,et al.  A Database of [11C]WAY-100635 Binding to 5-HT1A Receptors in Normal Male Volunteers: Normative Data and Relationship to Methodological, Demographic, Physiological, and Behavioral Variables , 2002, NeuroImage.

[48]  A. Pertovaara,et al.  Blood flow increase in the orofacial area of humans induced by painful stimulation , 1994, Brain Research Bulletin.

[49]  J. Alger,et al.  Brain responses associated with the Valsalva maneuver revealed by functional magnetic resonance imaging. , 2002, Journal of neurophysiology.

[50]  Kjell Någren,et al.  Measurement of Serotonin 5-HT1A Receptor Binding Using Positron Emission Tomography and [carbonyl-11C]WAY-100635—Considerations on the Validity of Cerebellum as a Reference Region , 2007 .

[51]  M. Diksic,et al.  Sex differences of brain serotonin synthesis in patients with irritable bowel syndrome using alpha-[11C]methyl-L-tryptophan, positron emission tomography and statistical parametric mapping. , 2003, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[52]  D. Zhuang,et al.  Involvement of 5-hydroxytryptamine1A receptors in the descending anti-nociceptive pathway from periaqueductal gray to the spinal dorsal horn in intact rats, rats with nerve injury and rats with inflammation , 2002, Neuroscience.

[53]  Sati Mazumdar,et al.  Serotonin 1A Receptor Binding and Treatment Response in Late-Life Depression , 2004, Neuropsychopharmacology.

[54]  E. Azmitia,et al.  Cellular Localization of the 5-HT1A Receptor in Primate Brain Neurons and Glial Cells , 1996, Neuropsychopharmacology.

[55]  F. Graeff,et al.  Role of 5-HT in stress, anxiety, and depression , 1996, Pharmacology Biochemistry and Behavior.

[56]  T. Shallice,et al.  Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. , 2003, Brain : a journal of neurology.

[57]  C. Halldin,et al.  Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[58]  S C Gandevia,et al.  Neural sites involved in the sustained increase in muscle sympathetic nerve activity induced by inspiratory capacity apnea: a fMRI study. , 2006, Journal of applied physiology.

[59]  F. Bloom,et al.  The Biochemical Basis of Neuropharmacology , 1976 .

[60]  C. Schmid,et al.  A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. , 1996, Arthritis and rheumatism.

[61]  P A Sargent,et al.  Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635. , 1996, European journal of pharmacology.