Spinal endocannabinoids and CB1 receptors mediate C-fiber-induced heterosynaptic pain sensitization.
Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain. Pathways that reduce synaptic inhibition in inflammatory and neuropathic pain states have been identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C-fiber) input to the spinal dorsal horn. We found that endocannabinoids, produced upon strong nociceptive stimulation, activated type 1 cannabinoid (CB1) receptors on inhibitory dorsal horn neurons to reduce the synaptic release of gamma-aminobutyric acid and glycine and thus rendered nociceptive neurons excitable by nonpainful stimuli. Our results suggest that spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain-controlling circuits.
Pernía-Andrade
Alejandro J
AJ
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Kato
Ako
A
Witschi
Robert
R
Nyilas
Rita
R
Katona
István
I
Freund
Tamás F
TF
Watanabe
Masahiko
M
Filitz
Jörg
J
Koppert
Wolfgang
W
Schüttler
Jürgen
J
Ji
Guangchen
G
Neugebauer
Volker
V
Marsicano
Giovanni
G
Lutz
Beat
B
Vanegas
Horacio
H
Zeilhofer
Hanns Ulrich
HU
D000328:Adult; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D004558:Electric Stimulation; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology*; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D009433:Neural Inhibition; D010146:Pain / Q000503:physiopathology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000502:physiology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology; D009435:Synaptic Transmission; D055815:Young Adult
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant