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Acute Reduction of Anandamide-Hydrolase (FAAH) Activity is Coupled With a Reduction of Nociceptive Pathways Facilitation in Medication-Overuse Headache Subjects After Withdrawal Treatment

Authors

  • Armando Perrotta MD, PhD,

    Corresponding author
    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
      A. Perrotta, Headache Clinic, IRCCS INM Neuromed, Via Atinense, 18, Pozzilli, Italy, email: arm.perrotta@gmail.com
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    • Contributed equally to this work.

  • Natalia Arce-Leal MD, PhD,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Cristina Tassorelli MD, PhD,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Valeria Gasperi PhD,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Grazia Sances MD,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Fabio Blandini MD, PhD,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Mariano Serrao MD, PhD,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Monica Bolla MD,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Francesco Pierelli MD, DrMSc,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Giuseppe Nappi MD, DrMSc,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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  • Mauro Maccarrone DrMSc,

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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    • Contributed equally to this work.

  • Giorgio Sandrini MD, DrMSc

    1. From the Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy (A. Perrotta and N. Arce-Leal); Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy (N. Arce-Leal, C. Tassorelli, and G. Sandrini); Headache Science Center, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy (C. Tassorelli, G. Sances, M. Bolla, G. Nappi, and Giorgio Sandrini); Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy (V. Gasperi); Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson's Disease, IRCCS National Institute of Neurology “C. Mondino,” Pavia, Italy (F. Blandini); Department of Medical and Surgical Science and Biotecnology, Sapienza University of Rome, Rome, Italy (M. Serrao and F. Pierelli); Department of Biomedical Sciences, University of Teramo, Teramo, Italy, and European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy (M. Maccarrone).
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    • Contributed equally to this work.


  • Conflict of Interest: No conflict of interests are declared by the authors.

  • Financial support: This study was supported by grants issued by the Italian Ministry of Health (RC2009 to G.S.) and partly by Fondazione Cassa di Risparmio di Teramo (research grant 2009-2012 to M.M.).

A. Perrotta, Headache Clinic, IRCCS INM Neuromed, Via Atinense, 18, Pozzilli, Italy, email: arm.perrotta@gmail.com

Abstract

Objectives.— We investigated (1) a possible relationship between the functional activity of the endocannabinoid system and the facilitation of pain processing in migraineurs with medication-overuse headache, and (2) the effect of withdrawal treatment on both.

Background.— The endocannabinoid system antinociception effect includes prevention of nociceptive pathways sensitization. The sensitization of the pain pathways has been demonstrated to be pivotal in the development and maintenance of chronic form of migraine, including medication-overuse headache.

Methods.— We used the temporal summation threshold of the nociceptive withdrawal reflex to explore the spinal cord pain processing, and the platelet activity of the enzyme fatty acid amide hydrolase to detect the functional state of the endocannabinoid system in 27 medication-overuse headache subjects before and 10 and 60 days after a standard withdrawal treatment and compared results with those of 14 controls.

Results.— A significantly reduced temporal summation threshold and increased related pain sensation was found in subjects before withdrawal treatment when compared with controls. A significant fatty acid amide hydrolase activity reduction coupled with a significant improvement (reduction) in facilitation of spinal cord pain processing (increase in temporal summation threshold and reduction in related pain sensation) was found in medication-overuse headache subjects at both 10 and 60 days after withdrawal treatment when compared with medication-overuse headache subjects before withdrawal treatment.

Conclusions.— We demonstrated a marked facilitation in spinal cord pain processing in medication-overuse headache before withdrawal treatment when compared with controls. Furthermore, the acute reduction of the fatty acid amide hydrolase activity coupled with a reduction of the facilitation in pain processing immediately (10 days) after withdrawal treatment and its persistence 60 days after withdrawal treatment could represent the consequence of a mechanism devoted to acutely reduce the degradation of endocannabinoids and aimed to increase the activity of the endocannabinoid system that results in an antinociceptive effect.

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