Early origin of sweet perception in the songbird radiation.

Early events in the evolutionary history of a clade can shape the sensory systems of descendant lineages. Although the avian ancestor may not have had a sweet receptor, the widespread incidence of nectar-feeding birds suggests multiple acquisitions of sugar detection. In this study, we identify a single early sensory shift of the umami receptor (the T1R1-T1R3 heterodimer) that conferred sweet-sensing abilities in songbirds, a large evolutionary radiation containing nearly half of all living birds. We demonstrate sugar responses across species with diverse diets, uncover critical sites underlying carbohydrate detection, and identify the molecular basis of sensory convergence between songbirds and nectar-specialist hummingbirds. This early shift shaped the sensory biology of an entire radiation, emphasizing the role of contingency and providing an example of the genetic basis of convergence in avian evolution.

Involvement of inflammation in severe post-operative pain demonstrated by pre-surgical and post-surgical treatment with piroxicam and ketorolac.

OBJECTIVES: Post-operative pain is considered to involve inflammation caused by tissue injury. However, the mechanism and timing of the involvement of inflammation in the post-operative pain remain complicated because they can vary among different types of surgery. In this study a rat incision model was used to investigate how inflammation induced by cyclooxygenases (COXs) is involved in severe post-operative pain. METHODS: Longitudinal incision with a length of 1cm was made through skin and fascia on the right hind paw of rats, starting 0.5cm from the edge of the heel and extending towards the toes. Allodynia was evaluated using the von Frey hair test and its degree was recorded as the paw withdrawal threshold (PWT). Two non-steroidal anti-inflammatory drugs (NSAIDs), piroxicam and ketorolac, were given to rats after or before surgery, and the effects of the drugs on allodynia induced by the hind paw incision were examined. KEY FINDINGS: The PWT reduction reached a sub-maximal level at 3h, a maximal level at one day after the surgery and lasted for more than 8 days, with the parallel development of inflammation (characterized by cell infiltration and oedema). Treatment with morphine (1mg/kg, s.c.) at one day after the surgery showed a significant anti-allodynic effect. Treatment with either piroxicam (10mg/kg, p.o.) or ketorolac (10mg/kg, p.o.) at one day after the surgery did not exhibit significant anti-allodynic effect, whereas pre-surgical treatment with each drug showed significant anti-allodynic effects at 3h after surgery. CONCLUSIONS: These findings suggest the involvement of cyclooxygenases in evoking pain that occurs in the immediate post-operative period, and that an initial suppression of rapid inflammation by treatment with NSAIDs before major surgery plays an important role in the management of severe post-operative pain.

Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493'.

A novel central nervous system (CNS) selective neurokinin-1 (NK(1)) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine 'CJ-17,493' (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K(i)=0.2 nM) for the human NK(1) receptor in IM-9 cells, potent activity in the [Sar(9), Met(O(2))(11)]SP-induced gerbil tapping model (ED(50)=0.04 mg/kg, s.c.) and in the ferret cisplatin (10mg/kg, i.p.)-induced anti-emetic activity model (vomiting: ED(90)=0.07 mg/kg, s.c.), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.

Effect of prostanoid EP4 receptor antagonist, CJ-042,794, in rat models of pain and inflammation.

Recent study suggests that the proinflammatory and nociceptive effects of prostaglandin E(2) are mediated by prostanoid receptor subtype EP(4) and prostanoid EP(4) receptor may be a potential target for the treatment of inflammatory pain. Here we describe pharmacological characterization of a novel prostanoid EP(4) receptor antagonist, CJ-042,794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl) oxy] phenyl} carbonyl) amino] ethyl} benzoic acid) in comparison with piroxicam (non-steroidal anti-inflammatory drug) or rofecoxib (cyclooxygenase-2 inhibitor). CJ-042,794 competitively antagonized cAMP accumulation with a pA(2) value of 8.7 in HEK293 cells overexpressing rat prostanoid EP(4) receptors. Orally administered CJ-042,794 dose-dependently inhibited carrageenan-induced mechanical hyperalgesia with an ED(50) value of 4.7 mg/kg (11 micromol/kg) and its maximal activity was somewhat less effective than that of 10 mg/kg piroxicam (30 micromol/kg p.o.). When CJ-042,794 and rofecoxib were administered to adjuvant-induced arthritis rats on Days 12-22 twice daily, both compounds reversed paw swelling to normal levels. These results suggest that a pharmacological blockade of the prostanoid EP(4) receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.

Mathematical analysis of involvement ratio between central and peripheral COX-2 in rat pain models with two types of COX-2 inhibitors with different distribution, celecoxib and CIAA.

The purpose of this study is to clarify involvement ratios between central and peripheral cyclooxygenase (COX)-2 in rat inflammatory pain models, by evaluating celecoxib and [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid (CIAA) on carrageenan-induced mechanical and thermal hyperalgesia. Celecoxib and CIAA exhibited ID(30) values with 1.5 and 7.7 mg/kg on mechanical hyperalgesia, respectively, and ID(25) values with 0.54 and 36 mg/kg on thermal hyperalgesia, respectively. By solving quadratic functional analysis with prostaglandin E(2) (PGE(2)) inhibitory activities, it was calculated that involvement ratios between central and peripheral COX-2 involvement were 0.47 and 0.53 on mechanical hyperalgesia, and 0.97 and 0.03 on thermal hyperalgesia, respectively. These data suggest that central and peripheral COX-2 are equally involved in mechanical hyperalgesia, while central COX-2 is predominantly involved in thermal hyperalgesia.

Differential involvement of TRPV1 receptors at the central and peripheral nerves in CFA-induced mechanical and thermal hyperalgesia.

Transient receptor potential vanilloid 1 (TRPV1) antagonists are known to attenuate two typical symptoms of inflammatory hyperalgesia: thermal and mechanical. However, it is not clear whether the sites of participation of TRPV1 for each symptom are different. In this study, we clarified the difference between the site of TRPV1 involvement in both symptoms by analysing the anti-hyperalgesic activity of two kinds of TRPV1 antagonists given locally (i.e. intraplantarly and intrathecally) in rats with CFA (complete Freund's adjuvant)-induced inflammation. TRPV1 antagonists BCTC (N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide, 1-300 microg) and SB-366791 (N-(3-methoxyphenyl)-4-chlorocinnamide, 30-300 microg) administered intraplantarly in a dose-dependent manner inhibited CFA-induced thermal hyperalgesia. In addition, CFA-induced thermal hyperalgesia was significantly reversed by intrathecal administration of 1-100 microg of BCTC and SB-366791. While intraplantar BCTC (1-300 microg) and SB-366791 (30-300 microg) did not reverse CFA-induced mechanical hyperalgesia, 1-100 microg of intrathecally administered BCTC and SB-366791 dose-dependently reduced mechanical hyperalgesia. Regression analysis showed that a correlation exists between the inhibitory effects on thermal hyperalgesia and mechanical hyperalgesia after intrathecal administration (correlation factor = 0.6521), but not after intraplantar administration (correlation factor = 0.0215). These data suggest that TRPV1 in the peripheral endings of the primary afferents plays a key role in thermal hyperalgesia, but it makes only a minor contribution in CFA-induced mechanical hyperalgesia. Furthermore, it is suggested that the spinal TRPV1 is critical in the development of both types of hyperalgesia.

Pharmacological separation between peripheral and central functions of cyclooxygenase-2 with CIAA, a novel cyclooxygenase-2 inhibitor.

There are many reports concerning the physiological and pathological involvement of cyclooxygenase (COX)-2 in the central nervous system and peripheral tissue cells. Selective COX-2 inhibitors that mainly distribute peripherally have not been reported thus far. Therefore central and peripheral roles of COX-2 remain classified pharmacologically. In this study, in vivo pharmacological profiles of CIAA ([6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid), a novel selective COX-2 inhibitor which distributes at higher concentrations in plasma than in brain, were compared with those of well-known selective COX-2 inhibitors, celecoxib and rofecoxib. Additionally, the possibility of pharmacological separation between peripheral and central actions of COX-2 with the inhibitors was investigated. CIAA selectively inhibited COX-2 activity compared with COX-1 in in vitro assays with rat whole blood. The compound exhibited lower brain penetration and higher plasma concentration (the brain/plasma concentration ratio was approximately 0.02) than celecoxib and rofecoxib after oral administration. Therefore, CIAA is mainly expected to act peripherally. Edema and prostaglandin E2 (PGE2) production in Carrageenan-injected rat paws, and pyrexia and PGE2 production in the brain in lipopolysaccharide (LPS)-injected rats were measured in in vivo experiments. CIAA exhibited lower ratios of anti-pyretic/anti-edematous activities and of inhibitory activities of PGE2 production in brain/paw than those of celecoxib and rofecoxib, and these ratios well-reflected brain/plasma concentration ratios. In conclusion, we discovered a novel selective COX-2 inhibitor, CIAA, which distributes at higher concentrations in plasma than in brain, which would make possible the pharmacological separation of the peripheral and central functions of COX-2.

A tachykinin NK1 receptor antagonist attenuates the 4 beta-phorbol-12-myristate-13-acetate-induced nociceptive behaviour in the rat.

Antinociceptive effect of a tachykinin NK1 receptor antagonist ezlopitant [(2S,3S-cis)-2-(diphenylmethyl)-N-{(2-methoxy, 5-isopropylphenyl)methyl}-1-azabicyclo[2.2.2]octan-3-amine] was investigated in the 4beta-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive test in the rat. Intraplantar injection of PMA-induced paw-licking and flinching behaviour lasted up to 120 min and was accompanied by inflammatory reactions, such as swelling and invasion of granulocytes. Pretreatment with resiniferatoxin [200 microg/kg, subcutaneous (s.c.)] blocked the PMA-induced nociceptive behaviour, suggesting that vanilloid VR1 receptor-expressing primary sensory neurons play a major role in this response. Subcutaneous pretreatment with ezlopitant (0.3-30 mg/kg) and morphine (0.3-6 mg/kg) caused a dose-dependent inhibition of the behaviour. Ezlopitant (3-30 mg/kg) given subcutaneously after PMA injection also significantly attenuated the behavioural response. When administered intrathecally, ezlopitant and a nonselective glutamate receptor antagonist MK-801 had an inhibitory effect, whereas CJ-12,191, an inactive isomer of ezlopitant, was unaffected. These results suggest that spinal tachykinin NK1 receptors contribute to processing of ongoing pain associated with peripheral inflammation.