1 We have characterised the effects of piperine, a pungent alkaloid found in black pepper, on the human vanilloid receptor TRPV1 using whole-cell patch-clamp electrophysiology. 2 Piperine produced a clear agonist activity at the human TRPV1 receptor yielding rapidly activating whole-cell currents that were antagonised by the competitive TRPV1 antagonist capsazepine and the non-competitive TRPV1 blocker ruthenium red. 3 The current-voltage relationship of piperine-activated currents showed pronounced outward rectification (2574-fold between À70 and þ 70 mV) and a reversal potential of 0.070.4 mV, which was indistinguishable from that of the prototypical TRPV1 agonist capsaicin. 4 Although piperine was a less potent agonist (EC 50 ¼ 37.971.9 mM) than capsaicin (EC 50 ¼ 0.2970.05 mM), it demonstrated a much greater efficacy (approximately two-fold) at TRPV1. 5 This difference in efficacy did not appear to be related to the proton-mediated regulation of the receptor since a similar degree of potentiation was observed for responses evoked by piperine (230720%, n ¼ 11) or capsaicin (284732%, n ¼ 8) upon acidification to pH 6.5. 6 The effects of piperine upon receptor desensitisation were also unable to explain this effect since piperine resulted in more pronounced macroscopic desensitisation (t 1/2 ¼ 9.970.7 s) than capsaicin (t 1/2 420 s) and also caused greater tachyphylaxis in response to repetitive agonist applications. 7 Overall, our data suggest that the effects of piperine at human TRPV1 are similar to those of capsaicin except for its propensity to induce greater receptor desensitisation and, rather remarkably, exhibit a greater efficacy than capsaicin itself. These results may provide insight into the TRPV1-mediated effects of piperine on gastrointestinal function.

D 1A -null mice were backcrossed over 14 generations into a C57BL/6 background to result in essential elimination (to o0.005%) of any contribution from the 129/Sv component of their initially mixed (129/Sv  C57BL/6) background. Their phenotype was assessed using an ethologically based approach that resolves each individual topography of behaviour in the natural repertoire. Habituation of sniffing, locomotion, rearing seated, and rearing to wall in wild types over several hours was profoundly retarded in congenic D 1A mutants; conversely, rearing free and sifting were essentially abolished. Resultant increases in individual topographies of behaviour were substantially greater in congenic D 1A mutants than in those on a mixed background. This phenotype was little altered by the selective

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Uncertainty as to the functional role of the D(3) dopamine receptor, due primarily to a paucity of selective agonists or antagonists, is being addressed in mice with targeted gene deletion ("knockout") thereof. This study describes, for the first time, the phenotype of congenic D(3)-null mice. Initially, 129/Sv x C57BL/6 D(3)-null mice were backcrossed 14 times onto C57BL/6; they were then assessed using an ethologically based approach which resolves all topographies of behaviour within the mouse repertoire. The ethogram of D(3)-null mice, on comparison with wildtypes, was characterised by no alteration in any topography of behaviour over an initial period of exploration; subsequent assessment over several hours revealed only increased rearing among females due to delayed habituation. Low doses of the selective D(2)-like agonist RU 24213 (0.016-0.25 mg/kg) inhibited topographies of exploratory behaviour; this effect was diminished in D(3)-null mice only when investigated following prolonged habituation, and then only for certain topographies of behaviour, primarily sniffing and rearing. High doses of RU 24213 (0.1-12.5 mg/kg) induced stereotyped sniffing and "ponderous" locomotion, while the selective D(1)-like agonist SK&F 83959 (0.016-2.0 mg/kg) promoted characteristic grooming syntax; these effects did not differ materially between the genotypes. When examined topographically on an essentially congenic C57BL/6 background (<0.005% 129/Sv), the resultant phenotype indicated essential conservation of the mouse ethogram, high-dose D(2)-like stimulatory effects, and D(1)-like stimulatory effects in the absence of D(3) receptors. A role for D(3) receptors in inhibitory processes appeared topographically circumscribed and only when baseline levels of behaviour were low.

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