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Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

Nature Neuroscience volume 10, pages870–879(2007)Cite this article

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.

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Figure 1: Demonstration of conditional deletion of CB1 specifically in nociceptive neurons of the DRG in sensory neuron–specific CB1 knockout mice (SNS-CB1−).
Figure 2: Expression of CB1 mRNA and CB1 protein is similar in the brain and spinal cord of CB1fl mice and SNS-CB1− mice.
Figure 3: Nociceptive responses, locomotive performance and nociceptive activity–induced expression of proteins in SNS-CB1− mice and their CB1fl littermates.
Figure 4: Analysis of endocannabinoid levels in the paws and spinal segments (L4–L6) of SNS-CB1− mice, CB1fl mice, global CB1− mice and their wild-type controls (n = 6 each) in the basal state (naive) or in wild-type mice after injection of CFA into the hindpaw.
Figure 5: Behavioral and electrophysiological analysis of SNS-CB1− mice in models of inflammatory pain.
Figure 6: Effects of a systemically applied CB1/CB2-agonist, WIN, on inflammation-induced mechanical hypersensitivity and immobilization behavior.
Figure 7: Effects of WIN.
Figure 8: Endocannabinoid levels, pain behavior and analgesic effects of WIN in SNS-CB1− mice and CB1fl mice in the SNI model for neuropathic pain.

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Acknowledgements

The authors are grateful towards H.-J. Wrede and J. Harvey-White for expert technical assistance and towards S. Offermanns for comments on an earlier version of this manuscript. This work was supported by an Emmy Noether Program grant and a Klinische Forschergruppe 107 grant from the Deutsche Forschungsgemeinschaft (DFG) to R.K., a DFG grant to B.L., US National Institutes of Health (NIH) grants NS039518 and NS 038253 to C.J.W. and DA11322 and DA00286 to K.M., an Intramural Research Program grant of NIH to P.P. and G.K., and a P18444 grant from the Fonds zur Förderung der Wissenschaftlichen Forschung to M.K.

Author information

Author notes

  1. Pal Pacher, Irmgard Tegeder and Fumimasa Amaya: These authors contributed equally to this work.

Affiliations

  1. Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld, Heidelberg, 69120, Germany

    Nitin Agarwal, Christoph W Michalski & Rohini Kuner

  2. Laboratory of Physiological Studies, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane, MSC 9413, Bethesda, 20892-9413, Maryland

    Pal Pacher, Sandor Batkai & George Kunos

  3. Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main, 60590, Germany

    Irmgard Tegeder & Claudiu Marian

  4. Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Massachusetts General Hospital–East, Charlestown, 02129, Massachusetts, USA

    Fumimasa Amaya, Gary J Brenner & Clifford J Woolf

  5. Division of Physiology, Department for Physiology and Medical Physics, Innsbruck Medical University, Fritz-Preglstr.3, A-6020, Austria

    Cristina E Constantin & Michaela Kress

  6. Department of Structural and Functional Biology, Pharmacology Section and Neuroscience Center, University of Insubria, via A. da Giussano 1021052 Busto Arsizio (VA), Italy

    Tiziana Rubino & Daniela Parolaro

  7. Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, Mainz, 55099, Germany

    Giovanni Marsicano, Krisztina Monory & Beat Lutz

  8. Department of Anesthesiology, University of Washington School of Medicine, Seattle, 98195-6540, Washington, USA

    Ken Mackie

  9. Institute of Physiology & Pathophysiology, Universität of Erlangen, Universitätsstr. 17, Erlangen, D-91054, Germany

    Michael J Fischer & Peter Reeh

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  1. Nitin Agarwal
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Correspondence to Rohini Kuner.

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Supplementary information

Supplementary Fig. 1

Normal development of acute and pathological pain in SNS-Cre mice as compared with wild-type littermates. (PDF 80 kb)

Supplementary Fig. 2

Effects of WIN 55,212-2 (WIN), applied via intraplantar route of administration on inflammation-induced mechanical hypersensitivity in CB1−/− mice and their wild-type littermates. (PDF 66 kb)

Supplementary Fig. 3

Analysis of SNS-CB1−/− mice and CB1fl/fl mice in the spared nerve injury (SNI) model for neuropathic pain. (PDF 70 kb)

Supplementary Methods (PDF 137 kb)

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Agarwal, N., Pacher, P., Tegeder, I. et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci 10, 870–879 (2007). https://doi.org/10.1038/nn1916

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