title: Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors.
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.
authors.affiliation: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld, Heidelberg, 69120 Germany.
authors.forename: Nitin
authors.initials: N
authors.lastname: Agarwal
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.forename: Fumimasa
authors.initials: F
authors.lastname: Amaya
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Constantin
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Brenner
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Michalski
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Claudiu
authors.initials: C
authors.lastname: Marian
authors.forename: Sandor
authors.initials: S
authors.lastname: Batkai
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fischer
authors.forename: Peter
authors.initials: P
authors.lastname: Reeh
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.forename: Michaela
authors.initials: M
authors.lastname: Kress
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
mesh_terms: D000483:Alleles; D000698:Analgesia; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000502:physiology; D002186:Cannabinoids / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects; D017931:DNA Primers; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects*; D017933:Peripheral Nervous System / Q000187:drug effects*; D010523:Peripheral Nervous System Diseases / Q000473:pathology; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000235:genetics
chemical_list: D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D017931:DNA Primers; D043884:Receptor, Cannabinoid, CB1