1 The pharmacological pro®le was studied of MEN 11420, or cyclo{[Asn(b-D-GlcNAc)-Asp-Trp-PheDap-Leu]cyclo(2b-5b)}, a glycosylated derivative of the potent, selective, conformationally-constrained tachykinin NK 2 receptor antagonist MEN 10627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2b-5b)). and ion channels. 4 In the rabbit isolated pulmonary artery and rat urinary bladder MEN 11420 potently and competitively antagonized tachykinin NK 2 receptor-mediated contractions (pK B =8.6+0.07, n=10, and 9.0+0.04, n=12; Schild plot slope=71.06 (95% c.l.=71.3; 70.8) and 71.17 (95% c.l.=71.3; 71.0), respectively). MEN 11420 produced an insurmountable antagonism at NK 2 receptors in the hamster trachea and mouse urinary bladder. However, in both preparations, the eect of MEN 11420 was reverted by washout and an apparent pK B of 10.2+0.14, n= 9, and 9.8+0.15, n=9, was calculated in the hamster trachea and mouse urinary bladder, respectively. 5 MEN 11420 showed low anity (pK B 56) at guinea-pig and rat tachykinin NK 1 (guinea-pig ileum and rat urinary bladder) and NK 3 (guinea-pig ileum and rat portal vein) receptors. On the whole, the anities (potency and selectivity) showed by MEN 11420 for dierent tachykinin receptors, measured either in binding or in functional bioassays, were similar to those shown by the parent compound, MEN 10627. ) and intraduodenal (100 ± 300 nmol kg 71 ) administration of MEN 11420. MEN 11420 was more potent (about 10 fold) and longer lasting than its parent compound MEN 10627, possibly due to a greater metabolic stability. 7 A dose of MEN 11420 (100 nmol kg 71 , i.v.), that produced potent and long lasting inhibition of the contraction of the rat urinary bladder induced by challenge with the NK 2 selective receptor agonist [bAla 8 ]neurokinin A(4 ± 10) (10 ± 300 nmol kg 71 ), was without eect on the responses produced by the NK 1 receptor selective agonist [Sar 9 ]substance P sulphone (1 ± 10 nmol kg 71 ). 8 These ®ndings indicate that MEN 11420 is a potent and selective tachykinin NK 2 receptor antagonist. The introduction of a sugar moiety did not produce major changes in the anity pro®le of this antagonist as compared to MEN 10627, but markedly improved its in vivo potency and duration of action. With these characteristics, MEN 11420 is a suitable candidate for studying the pathophysiological signi®cance of tachykinin NK 2 receptors in humans.

Observational studies indicate that topical application of ricinoleic acid (RA), the main component of castor oil, exerts remarkable analgesic and anti-inflammatory effects. Pharmacological characterization has shown similarities between the effects of RA and those of capsaicin, suggesting a potential interaction of this drug on sensory neuropeptide-mediated neurogenic inflammation. The aim of this study was to assess RA anti-inflammatory activities in comparison with capsaicin in several models of acute and subchronic inflammation. The acute inflammation was induced by intradermal injection of carrageenan in the mouse or by histamine in the guinea-pig eyelid. In either experiment, the extent of the oedema thickness was measured. Subchronic oedema was induced by complete Freund's adjuvant injection in the ventral right paw of mice. Tissue substance P (SP) was measured in the carrageenan experiments by radioimmunoassay (RIA). It was found that the acute topical application of RA (0.9 mg/mouse) or capsaicin (0.09 mg/mouse) significantly increased the mouse paw oedema induced by carrageenan, while an 8-day repeated topical treatment with the same doses of both compounds resulted in a marked inhibition of carrageenan-induced paw oedema matched by a reduction in SP tissue levels. Similar effects were found against histamine-induced eyelid oedema in guinea-pigs after acute or repeated application of RA or capsaicin. RA and capsaicin given for 1-3 weeks reduced the established oedema induced by Freund's adjuvant, a subchronic model of inflammation, particularly if given by the intradermal route. Either in mouse paw or in guinea-pig eyelid, capsaicin but not RA by itself produced a slight hyperemia and activation of a behavioural response (e.g. scratching of the eyelids). On the basis of the present results, RA may be seen as a new capsaicin-like, non-pungent anti-inflammatory agent suitable for peripheral application.

Substance P (SP) and neurokinin A (NKA) are synthesized by enteric cholinergic motorneurons that project to the longitudinal and circular muscle of the mammalian intestine. Thus, acetylcholine, SP, and NKA are the excitatory neuromuscular transmitters in the intestine. Tachykinin NK1 and NK2 receptors are expressed by smooth muscle cells in most regions of the intestine: the corelease of SP and NKA from nerves thus realizes paradigms of tachykininergic cotransmission. Examples have been found in which a cooperative model can be applied to account for the action of SP-NKA acting at NK1 and NK2 receptors (e.g., circular muscle of guinea-pig duodenum), as well as examples in which the message produced by activation of the two receptors diverges sharply in producing responses that have a markedly different time course and use different effector systems (e.g., circular muscle of guinea-pig colon). NK3 receptors are expressed on both excitatory and inhibitory motor neurons: indirect contractions (via release of acetylcholine and tachykinins) and relaxations (via release of nitric oxide) can be evoked in the gut by selective stimulation of NK3 receptors. Although a role of NK3 receptors in certain enteric reflexes has been evidenced, the importance of this system in mediating hexamethonium-resistant enteric transmission appears less important than previously speculated.

We have investigated the pro- and anti-inflammatory effects of ricinoleic acid (RA), the main active principle of castor oil, in an experimental model of blepharitis induced by intradermal injection of carrageenan in the guinea-pig eyelid and its possible capsaicin-like mode of action on acutely dissociated rat dorsal root ganglia (DRG) neurons in vitro. Topical treatment with RA (10-100 mg/guinea-pig) or capsaicin (1-10 mg/guinea-pig) caused eyelid reddening and oedema. At lower doses (0.3-3 mg/guinea-pig and 0.009-0.09 mg/guinea-pig for RA and capsaicin, respectively) both drugs significantly potentiated the eyelid oedema induced by carrageenan. The tachykinin NK1 receptor antagonist FK 888 (0.59 mg/kg s.c.) abolished the potentiation of carrageenan-induced eyelid oedema induced by either RA or capsaicin. The neutral endopeptidase inhibitor, thiorphan (1.3 mg/kg i.v.) significantly enhanced the potentiation of carrageenan-induced eyelid oedema produced by RA. This potentiating effect was abolished by FK 888. Repeated (8 days) topical application of RA (0.9 mg/guinea-pig) or capsaicin (0.09 mg/guinea-pig) inhibited the carrageenan-induced eyelid oedema. This anti-inflammatory effect was accompanied by a reduction (75%-80% of SP and 46%-51% of NKA) in tachykinin content of the eyelids, as determined by radioimmunoassay. In dissociated rat DRG neurons, RA (0.1 mM for 5 min) significantly inhibited the inward currents induced by application of capsaicin (1 microM) and/or low pH (5.8), without inducing any currents by itself or changing voltage-dependent currents. Moreover, after 24-h incubation, RA (0.1 mM) significantly decreased the capsaicin (1 microM)-induced calcitonin gene-related peptide (CGRP) release from rat DRG neurons, whereas acute drug superfusion did not evoke CGRP release by itself. Summarizing, RA possesses capsaicin-like dual pro-inflammatory and anti-inflammatory properties which are observed upon acute and repeated application, respectively. However, unlike capsaicin, RA does not induce inward current in DRG neurons and it is devoid of algesic properties in vivo.