Cannabis has been demonstrated to have bronchodilator, antiinflammatory, and antitussive activity in the airways, but information on the active cannabinoids, their receptors, and the mechanisms for these effects is limited. We compared the effects of D 9-tetrahydrocannabinol, cannabidiol, cannabigerol, cannabichromene, cannabidiolic acid, and tetrahydrocannabivarin on contractions of the guinea pig-isolated trachea and bronchoconstriction induced by nerve stimulation or methacholine in anesthetized guinea pigs following exposure to saline or the proinflammatory cytokine, tumor necrosis factor a (TNF-a). CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl) phenol), a synthetic cannabinoid agonist, was also investigated in vitro. The cannabinoids were also evaluated on TNF-aand lipopolysaccharide-induced leukocyte infiltration into the lungs and citric acid-induced cough responses in guinea pigs. TNF-a, but not saline, augmented tracheal contractility and bronchoconstriction induced by nerve stimulation, but not methacholine. D 9 -Tetrahydrocannabinol and CP55940 reduced TNF-a2enhanced nerve-evoked contractions in vitro to the magnitude of saline-incubated trachea. This effect was antagonized by the cannabinoid 1 (CB 1 ) and CB 2 receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-caroxamide] and JTE907 [N-(1,3-benzodioxol-5-ylmethyl)-1,2-dihydro-7-methoxy-2-oxo-8-(pentyloxy)-3-quinolinecarboxamide], respectively. Tetrahydrocannabivarin partially inhibited the TNF-a2enhanced nerve-evoked contractions, whereas the other cannabinoids were without effect. The effect of cannabidiol and D 9-tetrahydrocannabinol together did not differ from that of the latter alone. Only -THC demonstrated effects on airway hyper-responsiveness, anti-inflammatory activity, and antitussive activity in the airways.

Background and Purpose Nausea is associated with the hormonal secretion of vasopressin and adrenaline, although their actions in inducing nausea is poorly understood. Here, we have investigated their actions on human stomach muscle. Experimental Approach Muscle strips were suspended in tissue baths and neuronal‐/non‐neuronally‐mediated contractions were measured. Custom software analysed eight motility parameters defining spontaneous phasic non‐neuronally mediated contractions. Receptor distributions were assessed by qPCR and immunofluorescence. Key Results V1A receptors and α1‐adrenoceptors were located on muscle as well as interstitial cells of Cajal (ICCs). Myogenic contractions of human proximal and distal stomach (respectively, 2.6 ± 0.1 and 2.7 ± 0.0 per minute; n = 44) were larger in the distal area (1.1 ± 0.1 and 5.0 ± 0.1 mN), developing relatively slowly (proximal) or rapidly (distal). Vasopressin caused tonic (proximal) or short‐lived (distal) increases in muscle tone and increased myogenic contraction amplitude, frequency and rate (acting at V1A receptors; thresholds 10−11–10−10 M); by contrast, cholinergically mediated contractions were unaffected. Oxytocin acted similarly to vasopressin but less potently, at OT receptors). Adrenaline increased (10−10–10−5 M; α1‐adrenoceptors) and decreased (≥10−6 M; β‐adrenoceptors) muscle tone and enhanced/reduced myogenic contractions. Cholinergically mediated contractions were reduced (α2‐adrenoceptors). Combined, vasopressin (10−9 M) and adrenaline (10−8 M) increased muscle tone and phasic myogenic activity in a synergistic manner. Conclusions and Implications Vasopressin and adrenaline increased human gastric tone and myogenic contraction amplitude, rate of contraction and frequency. In combination, their actions were further increased in a synergistic manner. Such activity may promote nausea.

Significance The global mortality, morbidity, and healthcare costs associated with cardiometabolic disease, including obesity, diabetes, hypertension, and dyslipidemia, are substantial and represent an expanding unmet medical need. Herein, we have identified a physiological role for C-type natriuretic peptide (CNP) in regulating key processes, including thermogenesis and adipogenesis, which combine to coordinate metabolic function and prevent the development of cardiometabolic disorders. This protective mechanism, which is in part mediated via an autocrine action of CNP on adipocytes, is underpinned by activation of cognate natriuretic peptide receptors (NPR)-B and NPR-C. This mechanism advances the fundamental understanding of energy homeostasis and glucose handling and offers the promise of improving the treatment of cardiometabolic disease.

Bergamot essential oil (BEO) added to food and drink promotes a citrus flavour. Folklore suggests benefits on gastrointestinal functions but with little supporting evidence. BEO and major constituents (linalool, limonene, linalyl acetate) were therefore examined for any ability to influence neuromuscular contractions of human and rat colon. Circular muscle strips (macroscopically-normal human colon obtained following ethical approval at cancer surgery; Sprague–Dawley rats) were suspended in baths (Krebs solution; 37 °C; 5% CO2 in O2) for measurement of neuronally-mediated contractions (prevented by tetrodotoxin or atropine) evoked by electrical field stimulation (5 Hz, 0.5 ms pulse width, 10s/minute, maximally-effective voltage), or contractions evoked by KCl (submaximally-effective concentrations). BEO and each constituent concentration dependently inhibited neuronally-mediated and KCl-induced contractions. In human: apparent pIC50 for BEO (volume/volume Krebs), respectively, 3.8 ± 0.3 and 4.4 ± 0.3; Imax 55.8% ± 4.2% and 37.5% ± 4.2%. For the constituents, the rank order of potency differed in human (linalool > limonene >> linalyl-acetate) and rat colon (linalyl-acetate > limonene = linalool), but rank order of efficacy was similar (linalool >> (BEO) = linalyl-acetate >> limonene). Thus, linalool had high efficacy but greater potency in human colon (Imax 76.8% ± 6.9%; pIC50 6.7 ± 0.2; n = 4) compared with rat colon (Imax 75.3% ± 1.9%; pIC50 5.8 ± 0.1; n = 4). The ability of BEO and linalool to inhibit human colon neuromuscular contractility provides a mechanism for use as complementary treatments of intestinal disorders.

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