Neuropharmacology
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In the rat subthalamic nucleus, which plays a critical role in the control of motor behaviour, specific binding of [3H]-prazosin was detected by radioligand binding to homogenates and by autoradiography in slices. [3H]-Prazosin binding to homogenates (Bmax 71 +/- 5 fmol/mg protein; Kd 0.27 +/- 0.05 nM) was competed for by alpha1-antagonists. In subthalamic nucleus slices and in the presence of 10 mM LiCl, noradrenaline (100 microM) produced a modest, but consistent, stimulation of [3H]-inositol phosphate accumulation (146 +/- 6% of basal), reversed by the alpha1-antagonist prazosin (1 microM). Extracellular single-unit recordings in slices showed that in a subpopulation (61 out of 94 cells) of rat subthalamic neurones with regular, single-spike firing pattern, noradrenaline induced a concentration-dependent increase in the firing rate (EC50 2.5 +/- 0.2 microM, maximum effect 272 +/- 33% of basal). ⋯ In four out of 11 neurones perfusion with 3 microM noradrenaline resulted in a shift from bursting to regular firing. Taken together, our results indicate that rat subthalamic neurones express alpha1-adrenoceptors responsible for noradrenaline-induced stimulation of the firing rate of a subpopulation of neurones. By modulating the spontaneous activity of STN neurones, noradrenergic pathways might have a significant role in regulating basal ganglia function and thus motor activity.
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Comparative Study
Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats.
The analgesic potential of cannabinoids may be hampered by their ability to produce aversive emotion when administered systemically. We investigated the hypothesis that the midbrain periaqueductal grey (PAG) is a common substrate mediating the anti-nociceptive and potential aversive effects of cannabinoids. The rat formalin test was used to model nociceptive behaviour. ⋯ The anti-nociceptive effect of HU210 is likely to result from activation of the descending inhibitory pain pathway. Mechanisms mediating the anti-aversive effects of cannabinoids in the PAG remain to be elucidated. These data implicate a role for the PAG in both cannabinoid-mediated anti-nociceptive and anti-aversive responses.
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Comparative Study
Intrathecal nerve growth factor restores opioid effectiveness in an animal model of neuropathic pain.
It is without dispute that the treatment of neuropathic pain is an area of largely unmet medical need. Available analgesics, such as morphine, either have minimal effects in neuropathic pain patients, or are not always well tolerated due to concurrent adverse effects. The chronicity of neuropathic pain is thought to be related to many neurochemical changes in the dorsal root ganglia (DRG) and spinal cord, including a reduction in the retrograde transport of nerve growth factor (NGF). ⋯ NGF. In addition, we demonstrate that i.t. morphine-induced antinociception was augmented by a cholecystokinin (CCK) antagonist in animals chronically infused with i.t. antibodies directed against NGF. We hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.
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Comparative Study
The effects of sham and full spinalization on the antinociceptive effects of NCX-701 (nitroparacetamol) in monoarthritic rats.
Nitric oxide (NO)-releasing NSAIDs have been shown to be safer and more potent as antinociceptive and anti-inflammatory agents than their parent compounds. NCX-701 (nitroparacetamol), in contrast to paracetamol, is an effective antinociceptive drug in normal animals but their effectiveness in monoarthritis has not been compared. We have now investigated this question by comparing the antinociceptive effects of i.v. ⋯ Sham spinalization reduced the effect of NCX-701 on nociceptive responses drastically. In spinalized animals, however, the effect was similar to that observed in intact animals, indicating a strong effect of NCX-701 at spinal sites, which counterbalances the decrease in the activity induced by the surgery. We conclude that NCX-701 is an effective antinociceptive drug in arthritic animals, with a mechanism of action located in the spinal cord, and different to that of paracetamol.
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General anaesthetics exhibiting enantioselectivity afford valuable tools to assess the fundamental mechanisms underlying anaesthesia. Here, we characterised the actions of the R-(+)- and S-(-)-enantiomers of etomidate. In mice and tadpoles, R-(+)-etomidate was more potent (approximately 10-fold) than S-(-)-etomidate in producing loss of the righting reflex. ⋯ S-(-)-etomidate exerted qualitatively similar, but weaker, actions. In a model of locomotor activity, fictive swimming in Xenopus laevis tadpoles, R-(+)- but not S-(-)-etomidate exerted a depressant influence via enhancement of GABAergic neurotransmission. Collectively, these observations strongly implicate the GABAA receptor as a molecular target relevant to the anaesthetic action of etomidate.