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      The brain signature of paracetamol in healthy volunteers: a double-blind randomized trial

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          Abstract

          Background

          Paracetamol’s (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans.

          Methods and results

          This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter.

          Conclusion

          These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain.

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          Most cited references 41

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          Descending control of pain.

           Mark J Millan (2002)
          Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
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            Why rejection hurts: a common neural alarm system for physical and social pain.

            Numerous languages characterize 'social pain', the feelings resulting from social estrangement, with words typically reserved for describing physical pain ('broken heart', 'broken bones') and perhaps for good reason. It has been suggested that, in mammalian species, the social-attachment system borrowed the computations of the pain system to prevent the potentially harmful consequences of social separation. Mounting evidence from the animal lesion and human neuroimaging literatures suggests that physical and social pain overlap in their underlying neural circuitry and computational processes. We review evidence suggesting that the anterior cingulate cortex plays a key role in the physical-social pain overlap. We also suggest that the physical-social pain circuitry might share components of a broader neural alarm system.
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              Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry.

               A Basbaum,  H Fields (1983)
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                23 July 2015
                : 9
                : 3853-3862
                Affiliations
                [1 ]CHU Clermont-Ferrand, Centre de Pharmacologie Clinique, Faculté de medicine, France
                [2 ]Centre d’Investigation Clinique – Inserm 1405, Faculté de medicine, France
                [3 ]Clermont Université, Laboratoire de Pharmacologie, Faculté de medicine, France
                [4 ]CHU Gabriel Montpied, Clermont-Ferrand, Service d’Imagerie Ostéo-articulaire thoracique et neurologique, Clermont-Ferrand, France
                [5 ]CHU Clermont-Ferrand, Délégation Recherche Clinique et à l’Innovation, Clermont-Ferrand, France
                [6 ]Institut du Cerveau et de la Moelle epiniere – ICM, Centre de NeuroImagerie de Recherche CENIR, Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC University Paris, Paris, France, Department of Neuroradiology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
                [7 ]UMR CNRS UdA 6284, Clemont-Ferrand, France
                Author notes
                Correspondence: Gisèle Pickering, Clinical Pharmacology Centre, Bâtiment 3C, CHU of Clermont-Ferrand, 58 Montalembert Road, 63001 Clermont-Ferrand cedex, France, Tel +33 4 7317 8416, Fax +33 4 7317 8412, Email gisele.pickering@ 123456udamail.fr
                Article
                dddt-9-3853
                10.2147/DDDT.S81004
                4517518
                26229445
                © 2015 Pickering et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                pain, pharmacology, fmri, nociception, paracetamol

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