Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors.
OBJECTIVE
Marijuana smoking is widespread in many countries, and the use of smoked synthetic cannabinoids is increasing. Smoking a marijuana joint leads to bronchodilation in both healthy subjects and asthmatics. The effects of Δ(9) -tetrahydrocannabinol and synthetic cannabinoids on human bronchus reactivity have not previously been investigated. Here, we sought to assess the effects of natural and synthetic cannabinoids on cholinergic bronchial contraction.


METHODS
Human bronchi isolated from 88 patients were suspended in an organ bath and contracted by electrical field stimulation (EFS) in the presence of the phytocannabinoid Δ(9) -tetrahydrocannabinol, the endogenous 2-arachidonoylglycerol, the synthetic dual CB1 and CB2 receptor agonists WIN55,212-2 and CP55,940, the synthetic, CB2 -receptor-selective agonist JWH-133 or the selective GPR55 agonist O-1602. The receptors involved in the response were characterized by using selective CB1 and CB2 receptor antagonists (SR141716 and SR144528 respectively).


RESULTS
Δ(9) -tetrahydrocannabinol, WIN55,212-2 and CP55,940 induced concentration-dependent inhibition of cholinergic contractions, with maximum inhibitions of 39, 76 and 77% respectively. JWH-133 only had an effect at high concentrations. 2-Arachidonoylglycerol and O-1602 were devoid of any effect. Only CB1 receptors were involved in the response because the effects of cannabinoids were antagonized by SR141716, but not by SR144528. The cannabinoids did not alter basal tone or contractions induced by exogenous Ach.


CONCLUSIONS
Activation of prejunctional CB1 receptors mediates the inhibition of EFS-evoked cholinergic contraction in human bronchus. This mechanism may explain the acute bronchodilation produced by marijuana smoking.
Laboratoire de Pharmacologie Respiratoire, UPRES EA220, Hôpital Foch, Suresnes, France; Laboratoire de Pharmacologie-Toxicologie, Hôpital Raymond Poincaré, Garches, France.
S
S
Grassin-Delyle
E
E
Naline
A
A
Buenestado
C
C
Faisy
J-C
JC
Alvarez
H
H
Salvator
C
C
Abrial
C
C
Advenier
L
L
Zemoura
P
P
Devillier
D000368:Aged; D000369:Aged, 80 and over; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D002186:Cannabinoids / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000235:genetics
D002186:Cannabinoids; C524885:GPR55 protein, human; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled
bronchi; cannabinoid; cholinergic fibres; humans; muscle contraction; receptors