Neuropharmacology
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The alpha(2)-adrenoceptors (alpha(2)-ARs) are located on primary afferent terminals and on neurons in the spinal cord dorsal horn. However, their relative contribution to the analgesic effect of the alpha(2)-AR agonists is not known. In this study, we determined the role of certain presynaptic alpha(2)-ARs in the antinociceptive effect produced by intrathecal administration of the alpha(2)-AR agonist clonidine. ⋯ Furthermore, in the vehicle-treated group, although intrathecal injection of clonidine produced a large increase in the thermal withdrawal latency, it only had a small and short-lasting effect on the mechanical withdrawal threshold. This study provides new information that the antinociceptive effect of spinally administered alpha(2)-AR agonists is largely modality-specific. Loss of TRPV1-expressing sensory neurons leads to a reduction in presynaptic alpha(2A)-ARs but paradoxically potentiates the effect of clonidine on mechano-nociception.
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Chronic muscle pain is a problem with high prevalence in clinical practice and its pharmacological treatment is difficult. There is a lack of animal models which reliably predict analgesic activity of drugs on muscle pain. Here we used intramuscular injection of tumor necrosis factor-alpha (TNF) in rats as a model of muscle pain. ⋯ In biceps muscle hyperalgesia, a significant reversal of hyperalgesia was seen with lacosamide at 10mg/kg. Significant effects were also seen for pregabalin and gabapentin at 100mg/kg. We could thus demonstrate in a rat model for myalgia that lacosamide effectively reduces muscular hyperalgesia and is somewhat more potent than gabapentin and pregabalin.
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The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. ⋯ Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.
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Compelling evidence has shown that in hippocampus tumor necrosis factor alpha (TNF-alpha) at pathological concentration inhibits long-term potentiation (LTP), a synaptic model of learning and memory. In the present work we investigated the role of TNF-alpha in LTP of C-fiber evoked field potentials in spinal dorsal horn, which is relevant to pathological pain. We showed that spinal application of TNF-alpha affected neither basal synaptic transmission mediated by C-fibers nor spinal LTP of C-fiber evoked field potentials induced by tetanic stimulation in intact rats. ⋯ Spinal application of JNK inhibitor (SP600125) or p38 MAPK inhibitor (SB203580) did not affect the spinal LTP induced by tetanic stimulation in intact rats, but completely blocked LTP induced by TNF-alpha in L5 VRT rats. NF-kappa B (NF-kappaB) inhibitor (PDTC) also blocked LTP induced by TNF-alpha. These results suggest that TNF-alpha and its downstream molecules may have no acute effect on spinal synaptic transmission in intact animals and induce LTP in rats with neuropathic pain produced by nerve injury.
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Here, we investigated changes in the free cytosolic Ca(2+) concentration ([Ca(2+)](i)), induced by the pharmacological activation of metabotropic glutamate receptors (mGluRs), in nociceptive neurons of the superficial spinal dorsal horn. Microfluorometric Ca(2+) measurements with fura-2 in a lumbar spinal cord slice preparation from young rats were used. Bath application of the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) resulted in a distinct increase of [Ca(2+)](i) in most of the neurons in superficial dorsal horn. ⋯ Inhibition of voltage-dependent L-type Ca(2+) channels (VDCCs) by verapamil or nicardipine reduced the (S)-3,5-DHPG-induced [Ca(2+)](i) rise likewise. Thus, in rat spinal cord, (S)-3,5-DHPG enhances Ca(2+) signalling in superficial dorsal horn neurons, mediated by the release of Ca(2+) from IP(3)-sensitive intracellular stores and by an influx through L-type VDCCs. This may be relevant to the processing of nociceptive information in the spinal cord.