A molecular basis of analgesic tolerance to cannabinoids.
Clinical usage of cannabinoids in chronic pain states is limited by their central side effects and the pharmacodynamic tolerance that sets in after repeated dosage. Analgesic tolerance to cannabinoids in vivo could be caused by agonist-induced downregulation and intracellular trafficking of cannabinoid receptors, but little is known about the molecular mechanisms involved. We show here that the type 1 cannabinoid receptor (CB1) interacts physically with G-protein-associated sorting protein 1 (GASP1), a protein that sorts receptors in lysosomal compartments destined for degradation. CB1-GASP1 interaction was observed to be required for agonist-induced downregulation of CB1 in spinal neurons ex vivo as well as in vivo. Importantly, uncoupling CB1 from GASP1 in mice in vivo abrogated tolerance toward cannabinoid-induced analgesia. These results suggest that GASP1 is a key regulator of the fate of CB1 after agonist exposure in the nervous system and critically determines analgesic tolerance to cannabinoids.
Tappe-Theodor
Anke
A
Pharmacology Institute, University of Heidelberg, 69120 Heidelberg, Germany.
Agarwal
Nitin
N
Katona
István
I
Rubino
Tiziana
T
Martini
Lene
L
Swiercz
Jakub
J
Mackie
Ken
K
Monyer
Hannah
H
Parolaro
Daniela
D
Whistler
Jennifer
J
Kuner
Thomas
T
Kuner
Rohini
R
D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002186:Cannabinoids / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004361:Drug Tolerance / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism
D000700:Analgesics; D002186:Cannabinoids; D002352:Carrier Proteins; C479636:Gprasp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D043884:Receptor, Cannabinoid, CB1