The capsaicin receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been reported that ATP, one of the inflammatory mediators, potentiates the VR1 currents evoked by capsaicin or protons and reduces the temperature threshold for activation of VR1 through metabotropic P2Y 1 receptors in a protein Kinase C (PKC)-dependent pathway, suggesting the phosphorylation of VR1 by PKC. In this study, direct phosphorylation of VR1 upon application of phorbol 12-myristate 13-acetate (PMA) was proven biochemically in cells expressing VR1. An in vitro kinase assay using glutathione S-transferase fusion proteins with cytoplasmic segments of VR1 showed that both the first intracellular loop and carboxyl terminus of VR1 were phosphorylated by PKC⑀. Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser 502 and Ser 800 were involved in the potentiation of the capsaicinevoked currents by either PMA or ATP. In the cells expressing S502A/S800A double mutant, the temperature threshold for activation was not reduced upon PMA treatment. The two sites would be promising targets for the development of substance modulating VR1 function, thereby reducing pain.The sensation of pain allows us to recognize injury and triggers appropriate protective responses. A specific population of primary afferent neurons called nociceptors are known to be involved in the detection of noxious thermal, mechanical, or chemical stimuli and can be distinguished by their sensitivity to capsaicin, the pungent ingredient in hot chili peppers (1-4). The capsaicin receptor VR1 1 is a nonspecific cation channel with six transmembrane domains expressed predominantly in unmyelinated C fibers and activated not only by capsaicin but also by noxious heat (with a thermal threshold Ͼ 43°C) or protons (acidification), both of which cause pain in vivo (5-9). This sensitivity of VR1 to multiple noxious stimuli might explain certain properties of so called polymodal nociceptors. Furthermore, analyses of mice lacking VR1 have shown that VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia, further suggesting a critical role for VR1 in the detection or modulation of pain (10, 11).Tissue damage associated with infection, inflammation, or ischemia produces an array of chemical mediators that activate or sensitize nociceptor terminals to elicit or exacerbate pain at the site of injury in addition to the release of the mediators from the niciceptor terminals themselves known as neurogenic inflammation. An important component of this pro-algesic response, adenosine 5Ј-triphosphate (ATP), has recently been found to potentiate the VR1 currents evoked by capsaicin or protons through metabotropic P2Y 1 receptor activation in a protein kinase C (PKC)-dependent pathway (12). In the presence of extracellular ATP, the temperature...

The capsaicin receptor, TRPV1 (VR1), is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. Extracellular Ca 2؉ -dependent desensitization of TRPV1 observed in patch-clamp experiments when using both heterologous expression systems and native sensory ganglia is thought to be one mechanism underlying the paradoxical effectiveness of capsaicin as an analgesic therapy. Here, we show that the Ca 2؉ -binding protein calmodulin binds to a 35-aa segment in the C terminus of TRPV1, and that disruption of the calmodulin-binding segment prevents TRPV1 desensitization. Compounds that interfere with the 35-aa segment could therefore prove useful in the treatment of pain.

No abstract

The effects of laryngeal mask airway (LMA) insertion and tracheal intubation on circulatory responses were studied in normotensive (n = 24) and hypertensive (n = 22) Les r$percussions de l'insertion du masque laryngd (ML) et de l~ntubation endotrachdale sur la circulation sont dtudides chez des normotendus (n = 24) et des hypertendus (n = 22). Au hasard et h double aveugle, le ML ou le tube endotrachdal est installd apr~s une induction au thiopentone avec relaxation musculaire ~ la succinylcholine. Comparativement aux niveaux initiaux, aussi bien chez les normo-que chez les hypertendus, la frdquence cardiaque (FC), la pression artirielle rnoyenne (PAM) et le produit frdquence-pression augmentent, clue ce soit aprbs l'intubation ou l~nsertion du ML (P < 0,05). Les changements hdmodynamiques sont plus prononcds apr~s l~ntuba-tion qu'aprbs l~nsertion du ML (P < 0,05). Aprbs l~ntubation de la trachde ou l~nsertion du MI_, chez l'hypertendu, la FC augmente de fafon plus marqude que chez le normotendu (P < 0,05). Les concentrations plasmatiques d'adrdnaline et de noradrdnaline augmentent apr~s l~ntubation ou l'insertion du ML comparativement aux valeurs initiales (P < 0,05) tant chez les normo-que chez les hypertendus. L'augmentation de la concentration de noradrdnaline apr~s l~ntubation est plus importante qu'aprds l~nsertion du ML (P < O,05,t Chez aucun des patients, on n'a ddceld dischdmie myocardique ~ I'ECG. Nous concluons que l~nsertion du ML est associde ?t des rdpercussions circulatoires moindres que l'intubation endotrach$ale aussi bien chez les norrno-que chez les hypertendus.Key words EQUIPMENT: laryngeal mask airway; [NTUBATION, TRACHEAL: complications; COMPLICATIONS' . tachycardia, hypertension. Accepted for publication 8th September, 1994. Laryngoscopy and tracheal intubation after induction of anaesthesia are frequently associated with transient hypertension, tachycardia and arrhythmias. Although these haemodynamic responses are probably of little consequence in healthy individuals, they may be more severe and more hazardous in hypertensive patients. ~ Laryngeal mask airway (LMA) insertion, originally described by Brain,2 has recently become widely used in airway management. 3 Insertion of the LMA after induction of anaesthesia causes less haemodynamic change than tracheal intubation. 4,5 However, the effects of LMA insertion after CAN J ANAESTH 1995 / 42:1 / pp 32-6

The magnitude of hemodynamic changes associated with tracheal intubation with the Trachlight is almost the same as that which occurs with the direct laryngoscope. Hemodynamic changes are likely to occur because of direct tracheal irritation rather than direct stimulation of the larynx.

complete response, defined as no PONV and no need for another rescue antiemetic, during 0-3 h after an-Dexamethasone decreases chemotherapy-induced aesthesia was 83% with granisetron and 98% with emesis when added to an antiemetic regimen. This granisetron plus dexamethasone, respectively (P= study was undertaken to evaluate the efficacy of gran-0.008); the corresponding incidence during 3-24 h after isetron/dexamethasone combination for preventing anaesthesia was 83% and 98% (P=0.008). No clinically postoperative nausea and vomiting (PONV) after lapimportant adverse events were observed in any of aroscopic cholecystectomy (LC). In a prospective, ranthe group. In conclusion, prophylactic therapy with domized, double-blind manner, 120 patients (83 granisetron/dexamethasone combination is more females), aged 25-65 years, were assigned to receive effective than granisetron alone for the prevention of granisetron 40 g kg −1 alone or granisetron 40 g kg −1 PONV after LC. plus dexamethasone 8 mg (n=60 of each) intravenously immediately before the induction of an-

Granisetron is effective in the prevention of retching and vomiting after strabismus repair and tonsillectomy in paediatric patients.

Objectives Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics. Methods Sixty‐three Japanese patients were classified into the following 3 genotype (phenotype) groups on the basis of polymerase chain reaction–restriction fragment length polymorphism analysis of CYP2C19 polymorphism: no variants, *1/*1 (extensive metabolizer [EM]); 1 variant, *1/*2 or *1/*3 (intermediate metabolizer [IM]); and 2 variants, *2/*2, *2/*3, or *3/*3 (poor metabolizer [PM]). We assessed the effects of these polymorphisms and of CYP3A4 mRNA content in the lymphocytes on the patients' recovery from general anesthesia. Results CYP2C19 genotyping analysis in the 63 subjects showed that 32%, 46%, and 22% of subjects were classified into the EM, IM, and PM groups, respectively. The PM subjects showed a larger area under the curve representing the concentration of diazepam over a 24‐hour period (AUC0–24) (2088 ± 378 ng/mL · h−1, P = .0259), lower clearance of diazepam (0.049 ± 0.009 L · h−1 · kg−1, P = .0287), and longer emergence time (median, 18 minutes; 25th‐75th percentile range, 13–21 minutes; P<.001) in comparison with subjects in the EM group (AUC0–24, 1412 ± 312 ng/mL; clearance, 0.074 ± 0.018 L · h−1 · kg−1; and emergence time, 10 minutes, 8–12 minutes [median and 25th‐75th percentile range]). The IM group also showed a longer emergence time (median, 13 minutes; 25th‐75th percentile range, 9–20 minutes; P<.001) and a larger variation in this parameter in comparison with the EM group. The distributions of the CYP2C19 genotype were significantly different between the 2 groups (rapid emergence < 20 minutes, slow emergence > 20 minutes) (P = .0148). The mean value of the CYP3A4 mRNA level in the slow‐emergence group (mean ± SD, 4.80 ± 3.99 ×10−10) was significantly lower than that of the rapid‐emergence group (mean ± SD, 12.50 ± 11.90 ×10−10) (P = .0315). However, there was no significant correlation between emergence time and CYP3A4 mRNA levels (r = 0.239, P = .0601). Conclusion We found that the CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia and that the slow‐emergence group possesses lower levels of CYP3A4 mRNA than are found in the rapid‐emergence group. Clinical Pharmacology & Therapeutics (2005) 78, 647–655; doi: