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Abstract: (−)-Δ9-Tetrahydrocannabinol has been demonstrated to have beneficial effects in the airways, but its psychoactive effects preclude its therapeutic use for the treatment of airways diseases. In the present study we have investigated the effects of (−)-cannabidiol, a non-psychoactive component of cannabis for its actions on bronchial smooth muscle in vitro and in vivo. Guinea-pig bronchial smooth muscle contractions induced by exogenously applied spasmogens were measured isometrically. In addition, contractile responses of bronchial smooth muscle from ovalbumin-sensitized guinea-pigs were investigated in the absence or presence of (−)-cannabidiol. Furthermore, the effect of (−)-cannabidiol against ovalbumin-induced airway obstruction was investigated in vivo in ovalbumin-sensitized guinea-pigs. (−)-Cannabidiol did not influence the bronchial smooth muscle contraction induced by carbachol, histamine or neurokinin A. In contrast, (−)-cannabidiol inhibited anandamide- and virodhamine-induced responses of isolated bronchi. A fatty acid amide hydrolase inhibitor, phenylmethanesulfonyl fluoride reversed the inhibitory effect of (−)-cannabidiol on anandamide-induced contractions. In addition, (−)-cannabidiol inhibited the contractile response of bronchi obtained from allergic guinea-pigs induced by ovalbumin. In vivo, (−)-cannabidiol reduced ovalbumin-induced airway obstruction. In conclusion, our results suggest that cannabidiol can influence antigen-induced airway smooth muscle tone suggesting that this molecule may have beneficial effects in the treatment of obstructive airway disorders. [Copyright &y& Elsevier]

1 Interactions between the cannabinoid system and the adenosine system were investigated in the myenteric plexus-longitudinal muscle (MPLM) of the guinea-pig ileum. 2 Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by exogenous adenosine and the adenosine receptor agonist 2-chloroadenosine. These inhibitory effect were reversed by the selective A[SUB1] receptor antagonist DPCPX (20 nM). 3 Preincubation of the MPLM with the cannabinoid receptor agonist CP55,940 (1 nM) or the endogenous cannabinoid ligand anandamide caused a significant leftward shift in the concentration-effect curves to adenosine and 2-chloroadenosine. 4 Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by the adenosine uptake inhibitor dipyridamole. The inhibition was reversed by DPCPX (20 nM). 5 Pretreatment with CP55,940 (1 nM) or anandamide (10 μM) significantly reduced the inhibition produced by dipyridamole, an effect which was completely reversed by the selective CB[SUB1] receptor ligand SR 141716 (100 nM). 6 Electrically evoked adenosine release, measured in real time by means of adenosine-specific biosensors, was inhibited by CP55,940 (10 nM). This inhibition was blocked when CP55,940 was applied in the presence of SR141716 (100 nM). 7 These results confirm the presence of presynaptic CB[SUB1] and A[SUB1] receptors in the guinea-pig MPLM, and suggest that CB[SUB1] receptor stimulation reduces electrically-evoked adenosine release. Overall the date raise the possibility that the cannabinoid system plays a role in the modulation of adenosine transmission in the MPLM. [ABSTRACT FROM AUTHOR]

1 GABA[sub B1] receptor subunit knockout mice were generated and the effects of the GABA[sub B] receptor agonist, baclofen, were evaluated within the peripheral nervous system (PNS) of wildtype (+/+), heterozygote (+/-) and knockout (-/-) animals. For this purpose, neuronallymediated responses were evoked in both the isolated ileum and urinary bladder, using selective electrical field stimulation (EFS). 2 In ileum resected from 4-8-week-old-mice, low frequencies of EFS (0.5 Hz) evoked irregular muscle contractions which were prevented by atropine 1 µM and reduced by baclofen (33.4 ± 5.6%, 100 µM). The latter effect was antagonized by the GABA[sub B] receptor antagonist CGP54626 0.2 µM. Baclofen 100 µM did not affect contractions of similar amplitude induced by carbachol, indicating that the ability of baclofen to inhibit cholinergic function in mouse ileum may be due to an action at prejunctional GABA[sub B] receptors. 3 To avoid the development of grand mal seizure by GABA[sub B1] (-/-) mice, a behaviour observed when the mice were greater than 3 weeks old, it was necessary to study the effects of this knockout in 1-3-week-old-animals. However, at this age, EFS at 0.5 Hz did not evoke robust muscle contractions. Consequently we used EFS at 5 Hz, which did evoke cholinergically mediated contractions, found to be of similar amplitude in (+/+) and (+/-) mice, of both 1-3 weeks and 4-8 weeks of age. At this frequency of EFS, baclofen reduced the amplitude of the evoked contractions [n = 6 (+/+) and n = 5 (+/-), IC[sub 50] 19.2 ± 4.8 µM) and this effect was greatly reduced in the presence of CGP54626 0.2 µM. 4 In urinary bladder from 1-3-week-old-mice, using higher frequencies of EFS to evoke clear, nerve-mediated contractions (10 Hz), baclofen 10-300 µM concentration-dependently inhibited contractions in (+/+) mice (IC[sub 50] 9.6 ± 3.8 µM). This effect was inhibited by CGP54626 (0.2 µM, 46... [ABSTRACT FROM AUTHOR]