Article abstract
Nature Neuroscience 10, 870 - 879 (2007)
Published online: 10 June 2007 | doi:10.1038/nn1916
Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors
Nitin Agarwal1, Pal Pacher2,10, Irmgard Tegeder3,10, Fumimasa Amaya4,10, Cristina E Constantin5, Gary J Brenner4, Tiziana Rubino6, Christoph W Michalski1, Giovanni Marsicano7, Krisztina Monory7, Ken Mackie8, Claudiu Marian3, Sandor Batkai2, Daniela Parolaro6, Michael J Fischer9, Peter Reeh9, George Kunos2, Michaela Kress5, Beat Lutz7, Clifford J Woolf4 & Rohini Kuner1
Abstract
Although endocannabinoids constitute one of the first lines of defense against pain, the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are uncertain. Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids. We deleted the type 1 cannabinoid receptor (CB1) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-specific loss of CB1 substantially reduced the analgesia produced by local and systemic, but not intrathecal, delivery of cannabinoids. We conclude that the contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.
- Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld, Heidelberg, 69120 Germany.
- Laboratory of Physiological Studies, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane, MSC 9413, Bethesda, Maryland 20892-9413.
- Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe Universität, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
- Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Massachusetts General Hospital–East, Charlestown, Massachusetts 02129, USA.
- Division of Physiology, Department for Physiology and Medical Physics, Innsbruck Medical University, Fritz-Preglstr.3 A-6020, Austria.
- Department of Structural and Functional Biology, Pharmacology Section and Neuroscience Center, University of Insubria, via A. da Giussano 1021052 Busto Arsizio (VA), Italy.
- Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, 55099 Mainz, Germany.
- Department of Anesthesiology, University of Washington School of Medicine, Seattle, Washington 98195-6540, USA.
- Institute of Physiology & Pathophysiology, Universität of Erlangen, Universitätsstr. 17, D-91054, Erlangen, Germany.
- These authors contributed equally to this work.
Correspondence to: Rohini Kuner1 e-mail: rohini.kuner@pharma.uni-heidelberg.de
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