Evidence for presynaptic cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the guinea pig lung

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Abstract

Using neurochemical method, evidence was obtained that cannabinoid CB1 receptors are localized on noradrenergic terminals and their stimulation by WIN-55,212-2 reduces the release of [3H]noradrenaline evoked by axonal activity in a frequency-dependent manner. At stimulation rates of 1 and 3 Hz, there was significant inhibition of noradrenaline release, with IC50 of WIN-55,212-2 41.5 ± 2.6 and 320.5 ± 28.2 nM, for 1 and 3 Hz, respectively. Cannabinoid CB1 receptor antagonist SR 141716A completely prevented WIN-55,212-2 from reducing the release. The release of noradrenaline is negatively modulated by presynaptic α2-adrenoceptors. Because BRL-44408, an α2B-adrenoceptor, and prazosin, an α1- and α2B-adrenoceptor antagonist, both increased the release of [3H]noradrenaline, it seems likely that the α2B subtype is responsible for the negative feedback modulation of noradrenaline release. In the presence of α2-adrenoceptor antagonism, cannabinoid CB1 receptor activation by WIN-55,212-2 was much more effective in inhibiting the release of [3H]noradrenaline. Using a specific antibody against the C-terminus of the rat cannabinoid CB1 receptor and also against neuropeptide Y, ultrastructural evidence was obtained that cannabinoid CB1 receptors are exclusively localized on neuropeptide Y-positive noradrenergic varicosities. Since the sympathetic innervation of the human airway smooth muscle is sparse, and mainly the circulating adrenaline relaxes the airways via activation of β2-adrenoceptor localized on the smooth muscle, it is suggested that inhibition of noradrenaline release by cannabinoids, and the subsequent bronchospasm, may be limited to those cases when noradrenaline released from sympathetic varicosities is involved in airway relaxation.

Original languageEnglish
Pages (from-to)237-244
Number of pages8
JournalEuropean Journal of Pharmacology
Volume431
Issue number2
DOIs
Publication statusPublished - nov. 16 2001

ASJC Scopus subject areas

  • Pharmacology

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