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We describe a new class of drugs that selectively block serotonin M-receptors on peripheral neurones. Because of their high affinity, some of these drugs are the most potent of any pharmacological class yet reported. They have allowed the identification of three M-receptor subtypes, one of which is responsible for mediating the painful effects of serotonin in humans.

The contractile effect of 5-HT in the isolated longitudinal ileal muscle of adult guinea-pigs was studied over a large concentration range. 5-HT produced a biphasic concentration-response curve indicative of an interaction with at least two independent populations of receptors. The concentrations which elicited half-maximal effects for the first and the second phases of the concentration-response curve were estimated as 1.5 +/- 1.2 X 10(-8) mol/l and 1.3 +/- 0.4 X 10(-6) mol/l respectively. The maximal response produced by the interaction of 5-HT with the high affinity receptor (i.e. first phase) was calculated as 27 +/- 9.3% of the total response. The biphasic concentration-response was not influenced by methysergide (10(-6) mol/l). The effect of low concentrations of 5-HT (less than 3 X 10(-7) mol/l) was antagonised by atropine (10(-7) mol/l), tetrodotoxin (TTX) (10(-6) mol/l), morphine (10(-5) mol/l), the substance P antagonist, D-Pro4,D-Trp7,9-SP4-11 (3 X 10(-5) mol/l) and capsaicin (10(-5) mol/l). Physostigmine (10(-7) mol/l) augmented the effect. The response to high concentrations of 5-HT (3 X 10(-7)-3 X 10(-6) mol/l) was antagonised by ICS 205-930 and D-Pro4,D-Trp7,9-SP4-11 in a competitive manner and was inhibited by TTX, morphine and capsaicin in an insurmountable way. The effect of very high concentrations of 5-HT (greater than 10(-5) mol/l) could be partially antagonised by methysergide (10(-7) mol/l) in the presence of ICS 205-930 (10(-7) mol/l) and totally by a combination of methysergide and TTX.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

e Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.