European journal of pharmacology
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Multicenter Study
The serotonin transporter gene polymorphism STin2 VNTR confers an increased risk of inconsistent response to triptans in migraine patients.
The aim of the present observational study was to assess the value of the C825T polymorphism of the beta-3 subunit of G proteins (GNB3) as well as of variants in the SLC6A4 gene (5HTTLPR and STin2 VNTR) and DRD2 gene (TaqI A and NcoI) as predictive markers for consistency in headache response to triptans in migraine patients. Consistent responders to triptans were defined as the migraineurs who experienced a > or =2 point reduction in a 4-point scale intensity of pain from 3 (severe) to 0 (absent) 2h after triptan administration, in at least two attacks out of the three. Genotyping was performed by PCR and PCR-RFLP on genomic DNA extracted from peripheral blood. ⋯ In a binary logistic regression model, STin 2.12/12 genotype (OR=3.363, 95% CI: 1.262-8.966, P=0.005) and non-use of migraine prophylactic medications (OR=2.848, 95% CI: 1.019-7.959, P=0.010) were found as significant factors increasing the odds of achieving inconsistent response to triptans. The analysis of classificatory power of the model showed moderate values of sensitivity (0.56), high specificity (0.87), and an overall prediction correctness (0.77). These results support the role of STin2 VNTR polymorphism of serotonin transporter gene as a relevant genetic factor conferring a higher risk of inconsistent response to triptans in migraine patients.
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The transient receptor potential vanilloid 1 (TRPV1) receptor is activated by noxious heat, various endogenous mediators and exogenous irritants. The aim of the present study was to compare three TRPV1 receptor antagonists (SB705498, BCTC and AMG9810) in rat models of heat hyperalgesia. The behavioural noxious heat threshold, defined as the lowest temperature evoking nocifensive reaction, was measured with an increasing-temperature water bath. ⋯ Plantar incision-induced heat threshold drop (7-8 degrees C) was dose-dependently diminished by an oral post-treatment with any of the antagonists with minimum effective doses of 10, 3 and 3mg/kg, respectively. Assessment of RTX hyperalgesia by measurement of the paw withdrawal latency with a plantar test apparatus yielded 30 mg/kg minimum effective dose for each antagonist. In conclusion, measurement of the noxious heat threshold with the increasing-temperature water bath is suitable to sensitively detect the effects of TRPV1 receptor antagonists in thermal hyperalgesia models.
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Comparative Study
Pre-treatment with capsaicin in a rat osteoarthritis model reduces the symptoms of pain and bone damage induced by monosodium iodoacetate.
A rat model of osteoarthritis was used to investigate the effect of pre-treatment with capsaicin on the symptoms of osteoarthritis induced by the injection of monosodium iodoacetate. This model mimics both histopathology and symptoms associated of human osteoarthritis. Injection of monosodium iodoacetate, an inhibitor of glycolysis, into the femorotibial joints of rodents promotes loss of articular trabecular bone and invokes pain symptoms similar to those noted in human osteoarthritis. ⋯ Decrease of bone volume was considerably ameliorated and trabecular connectivity was substantially better in capsaicin pre-treated animals. Capsaicin, an agonist activator of the vanilloid nociceptors (TRPV1), appears to be effective in protecting bone from arthritic damage. The present results support the hypothesis that capsaicin-sensitive sensory neurons contribute to bone lesions in the monosodium iodoacetate-induced osteoarthritis rat model.
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The periaqueductal gray (PAG) is a major component of the descending pain inhibitory pathway, which is related to central analgesia. In the present study, we have investigated the possible roles of presynaptic nicotinic acetylcholine receptors in GABAergic transmission onto PAG neurons. In acutely isolated rat PAG neurons, GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded by use of a whole-cell patch clamp technique. ⋯ The nicotine-induced increase in mIPSC frequency was completely occluded in the presence of Cd2+, a general voltage-dependent Ca2+ channels blocker, and in the absence of extracellular Ca2+ or Na+. The results suggest that presynaptic nicotinic receptors are less permeable to Ca2+, and that the activation of these receptors depolarizes GABAergic nerve terminals. In conclusion, presynaptic nicotinic receptors would temporally regulate the excitability of PAG neurons being not overexcited and eventually contribute to the cholinergic modulation of output from the PAG.
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We recently identified 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), the first allosteric metabotropic glutamate (mGlu) 7 receptor-selective negative allosteric modulator. In this study, we examined the in vivo pharmacological effects of MMPIP on the central nervous system. MMPIP was distributed into the brain after systemic administration in both mice and rats. ⋯ No analgesic effects of MMPIP were detected in either the tail immersion test or formalin test in mice. MMPIP did not alter the threshold for induction of seizures by electrical shock or pentylenetetrazole in mice. These findings suggest that blockade of mGlu(7) receptors by MMPIP may modulate both non-spatial and spatial cognitive functions without non-selective inhibitory effects on the central nervous system.