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Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers.
Olsen, RV, Andersen, HH, Møller, HG, Eskelund, PW, Arendt-Nielsen, L
European journal of pain (London, England). 2014;(9):1333-42
Abstract
BACKGROUND Activation of TRPM8 and TRPA1 receptors generates cold and cold pain sensations, respectively, and is presumably important in clinical pain manifestations, such as cold hyperalgesia. This study investigated the interaction between TRPM8 and TRPA1 receptors through stimulation of glabrous human skin (volar forearm) by topical administration of 40% L-menthol and 10% trans-cinnamaldehyde (CA), individually and in combination. METHODS Sensory manifestations were assessed in 10 healthy volunteers via a platform of 11 quantitative sensory (thermal and mechanical stimuli) and vasomotor tests (skin temperature, perfusion and axon-reflex-flare) in a double-blinded randomized crossover design. RESULTS Cold pain threshold was increased (p < 0.01, cold allodynia) by L-menthol alone and L-menthol + CA in combination but unaffected by CA. Mechanical pain threshold was significantly decreased (mechanical hyperalgesia) by all three substances (p < 0.01), with a significant intergroup difference found between CA alone and the less decreased L-menthol + CA (p < 0.05). Application of CA alone and L-menthol + CA in combination showed an increase in skin temperature and perfusion significantly larger than that induced by L-menthol alone (p < 0.05). An axon-reflex-flare was present after CA administration, but was significantly reduced upon addition of L-menthol (p < 0.01). CONCLUSION This study elucidates the potential of L-menthol as a counter-irritant to secondary neurogenic inflammation and provides evidence of an intricate interplay between cold receptors TRPA1 and TRPM8, warranting further investigation of the neural coding of cold pain perception.
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Effect of cigarette smoking on cough reflex induced by TRPV1 and TRPA1 stimulations.
Kanezaki, M, Ebihara, S, Gui, P, Ebihara, T, Kohzuki, M
Respiratory medicine. 2012;(3):406-12
Abstract
BACKGROUND Recent studies have shown that neurogenic inflammation induced by cigarette smoke is inhibited by TRPA1 antagonist, but not by TRPV1 antagonist. Since cough reflex sensitivity is known to be modified by smoking status, we investigated the effects of cigarette smoking on TRPA1- and TRPV1-induced cough and urge-to-cough in healthy males. METHODS Twenty-six healthy never-smokers and 30 healthy current smokers were recruited via public postings. Cough reflex thresholds and urge-to-cough were evaluated by inhalation of capsaicin, a TRPV1 agonist, and cinnamaldehyde, a TRPA1 agonist. The cough reflex thresholds were defined as the lowest concentrations of capsaicin and cinnamaldehyde that elicited two or more coughs (C(2)) and five or more coughs (C(5)), respectively. The urge-to-cough was evaluated using the modified Borg scale. RESULTS In capsaicin-induced cough, the cough reflex thresholds, as expressed by C(2) and C(5), in current smokers were significantly higher than those in never-smokers (p<0.01 and p<0.001, respectively). The urge-to-cough log-log slopes in current smokers were significantly lower than those of never-smokers (p<0.001). There were no significant differences in the thresholds of the urge-to-cough between never-smokers and current smokers. In cinnamaldehyde-induced cough, there were no significant differences in cough reflex thresholds in C(2) and C(5) between never-smokers and current smokers, nor were there any significant differences in urge-to-cough log-log slope between never-smokers and current smokers. There were no significant differences in the thresholds of the urge-to-cough between never-smokers and current smokers. CONCLUSION The study suggests that smoking has a differential effect on cough responses between TRPV1 and TRPA1 stimulations.
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TRP-channel-specific cutaneous eicosanoid release patterns.
Jain, A, Brönneke, S, Kolbe, L, Stäb, F, Wenck, H, Neufang, G
Pain. 2011;(12):2765-2772
Abstract
Analyzing mechanisms and key players in peripheral nociception nonneuronal skin cells are getting more and more into focus. Herein we investigated the functional expression of TRPV1 and TRPA1 in human keratinocytes and fibroblasts and assessed proinflammatory lipid mediator release upon their stimulation as well as sensory effects after topical application, combining in vitro and in vivo approaches. In vitro, the expression of functional TRPV1 and TRPA1 channels on fibroblasts and keratinocytes was confirmed via immunofluorescence, qualitative real time (RT) polymerase chain reaction, and cellular Ca(2+) influx measurements. Additionally, the agonists allyl isothiocyanate (TRPA1) and capsaicin (TRPV1) induce a differential secretion pattern of the eicosanoids PGE(2) and LTB(4) in human dermal fibroblasts and keratinocytes, which was also detectable invivo, analyzing suction blister fluid at various times after short-term topical application. Capsaicin provoked the release of LTB(4) at 2 and 24 hours. In contrast, PGE(2) levels were reduced upon stimulation. Allyl isothiocyanate, however, increased PGE(2) levels only at 24 hours, but did not alter LTB(4) levels. In parallel, heat pain thresholds were reduced by both agents after short-term topical application, but only AITC provoked a long-lasting local erythema. In conclusion, the agonist-induced activation of nociceptors by TRPA1 and TRPV1 elicits painful sensations, whereas nonneuronal tissue cells respond with differential release of inflammatory mediators, thus influencing local vasodilatation and neuronal sensitization. These results have implications for the application of transient receptor potential antagonists to improve inflammatory skin conditions and pain management.
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Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury.
Namer, B, Kleggetveit, IP, Handwerker, H, Schmelz, M, Jorum, E
Pain. 2008;(1):63-72
Abstract
Local cold injury often induces hypersensitivity to cold and cold allodynia. Sensitisation of TRPM8 or TRPA1 could be the underlying mechanisms. This was evaluated by psychophysics and axon-reflex-flare induction following topical menthol and cinnamaldehyde application in cold injury patients and healthy subjects. The patients had no signs of neuropathy except cold allodynia. We applied 20% cinnamaldehyde and 40% menthol solutions in the cold-allodynic area of the patients and in a corresponding area in healthy subjects and obtained sensory ratings during application. Thermotesting and Laser Doppler Imaging were performed before and after exposure to the compounds. Menthol did not induce axon-reflex-erythema in patients or in controls. After menthol cold pain threshold was decreased in healthy subjects; however, no further sensitisation was observed in the patients moreover in some patients an amelioration of their cold allodynia was observed. Cinnamaldehyde-induced pain sensation did not differ between patients and controls. Heat pain thresholds following cinnamaldehyde were lowered to a similar extent in patients and controls (43-39.8 and 44-39 degrees C) and also the axon-reflex-flare responses were comparable. No evidence for sensitisation of responses to TRPM8 or TRPA1-stimulation was found in patients with cold injury-induced cold allodynia. The lack of TRPM8 induced axon-reflex indicates that also de-novo expression of TRPM8 on mechano-insensitive C-nociceptors does not underlie cold allodynia in these patients. We conclude from these data that the mechanisms for the induction of cold allodynia in the patients with cold injury are independent of TRPM8 or TRPA1 and differ therefore from neuropathic pain patients.
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Teriparatide has no effect on the calcium-mediated pharmacodynamics of digoxin.
Benson, CT, Voelker, JR
Clinical pharmacology and therapeutics. 2003;(1):87-94
Abstract
BACKGROUND Teriparatide (recombinant human parathyroid hormone [1-34]) stimulates bone formation and causes small transient increases in serum calcium concentration. We assessed whether teriparatide causes a change in digoxin pharmacodynamic effects by measuring systolic time intervals and heart rate. METHODS Measurements were made by echocardiographic Doppler that examined 3 systolic time intervals, as follows: QS(2) (time from Q wave on electrocardiogram to the closure of the aortic valve), left ventricular ejection time, and pre-ejection period, all corrected for changes in heart rate. Fifteen healthy subjects (2 men and 13 women) were administered a single subcutaneous teriparatide dose (20 microg) on day 1 and then equilibrated on a daily oral dose of digoxin for 15 days. Subcutaneous placebo and teriparatide, 20 microg, were given in a randomized crossover design with the 14th (day 15) and 15th (day 16) digoxin doses. Serial systolic time interval and heart rate measurements were obtained on days 1, 15, and 16. RESULTS After subjects were dosed to steady state with digoxin, there were statistically significant reductions in QS(2) corrected for heart rate (QS(2)c) of 23 to 25 ms and heart rate of 4 to 6 beats/min. However, there was no difference between treatment with digoxin plus placebo versus digoxin plus teriparatide. The study was powered to find a difference in QS(2)c as small as 6 ms (alpha =.05, beta =.2). CONCLUSION Teriparatide, 20 microg subcutaneously, does not alter the cardiac effect of digoxin.
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6.
Effect of lacidipine and nifedipine GITS on platelet function in patients with essential hypertension.
Armas-Padilla, MC, Armas-Hernández, MJ, Hernández-Hernández, R, Velasco, M, Pacheco, B, Carvajal, AR, Castillo-Moreno, A
Journal of human hypertension. 2000;:S91-5
Abstract
With the aim of evaluating the effects on blood pressure, platelet function and insulin sensitivity of the dihydropiridines lacidipine and nifedipine GITS, a parallel double-blind study was carried out in a group of 20 patients with mild to moderate essential hypertension. They received a placebo for 4 weeks; then were divided at random into two groups of 10 patients each. Nifedipine GITS, 30 mg and lacidipine, 4 mg, were given during 16 weeks of active treatment. Blood pressure and heart rate were measured at the clinic in supine, sitting and standing positions, 24 +/- 1 h after the last dose. After the placebo and active phases were carried out, a platelet aggregation test was performed to determine platelet malondialdehyde production and a tolerance to 100 g of glucose by measuring glucaemia and plasma insulin. Both drugs reduced systolic and diastolic blood pressure at the same level, however there were observable differences in the rate of reduction. The nifedipine GITS reduced supine systolic blood pressure by 25 mm Hg in the first week, while the lacidipine did so by 11 mm Hg. At the end of the study period nifedipine reduced supine systolic blood pressure by 28 mm Hg and lacidipine by 20 mm Hg. Heart rate was increased slightly but significantly in the nifedipine GITS group only in the standing position. Both drugs reduced platelet aggregation ex vivo only marginally but they modified the malondialdehyde production, indicating an action on the arachidonic acid metabolic pathway.