Neuropharmacology
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To investigate the contribution of central vasopressin receptors to blood pressure (BP) and heart rate (HR) response to stress we injected non-peptide selective V(1a) (SR49059), V(1b) (SSR149415), V(2) (SR121463) receptor antagonists, diazepam or vehicle in the lateral cerebral ventricle of conscious freely moving rats stressed by blowing air on their heads for 2 min. Cardiovascular effects of stress were evaluated by analyzing maximum increase of BP and HR (MAX), latency of maximum response (LAT), integral under BP and HR curve (integral), duration of their recovery and spectral parameters of BP and HR indicative of increased sympathetic outflow (LF(BP) and LF/HF(HR)). Moreover, the increase of serum corticosterone was measured. ⋯ All drugs shortened the recovery period, prevented the increase of LF(BP) without affecting the increase in serum corticosterone levels. Results indicate that vasopressin receptors located within the central nervous system mediate, in part, the cardiovascular response to air-jet stress without affecting either the neuroendocrine component or inducing sedation. They support the view that the V(1b) receptor antagonist may be of potential therapeutic value in reducing arterial pressure induced by stress-related disorders.
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In the present study, the effects of bilateral injections of the GABAergic receptor agents into the dorsal hippocampal CA1 regions (intra-CA1) on morphine-induced amnesia were examined in morphine sensitized-mice. Pre-training subcutaneous (s.c.) administration of morphine (5 mg/kg) suppressed the learning of a one-trial passive avoidance task. Amnesia induced by pre-training morphine was significantly reversed in mice which had previously received once daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days, which may be due to behavioral sensitization. ⋯ However, the same treatment with GABAB receptor antagonist, CGP35348 (2.5-40 microg/mouse) had no effect on the morphine response. On the other hand, daily intra-CA1 injections of bicuculline or CGP35348 alone for 3 days did not alter the amnesia induced by pre-training injection of morphine. The results suggest that morphine sensitization reverses the impairment of memory induced by morphine and that GABAergic receptors of the dorsal hippocampus may play an important role in this effect.
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Acute morphine administration produces analgesia and reward, but prolonged use may lead to analgesic tolerance in patients chronically treated for pain and to compulsive intake in opioid addicts. Moreover, long-term exposure may induce physical dependence, manifested as somatic withdrawal symptoms in the absence of the drug. We set up three behavioral paradigms to model these adaptations in mice, using distinct regimens of repeated morphine injections to induce either analgesic tolerance, locomotor sensitization or physical dependence. ⋯ Finally, naloxone-precipitated morphine withdrawal did not enhance basal or forskolin-stimulated adenylate cyclase activity in nucleus accumbens, prefrontal cortex, amygdala, bed nucleus of stria terminalis or periaqueductal gray. Therefore, the expression of behavioral adaptations to chronic morphine treatment was not associated with the regulation of micro opioid receptor, cdk5 or adenylate cyclase activity in relevant brain areas. Although we cannot exclude that these modifications were not detected under our experimental conditions, another hypothesis is that alternative molecular mechanisms, yet to be discovered, underlie analgesic tolerance, locomotor sensitization and physical dependence induced by chronic morphine administration.
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Intrathecal (IT) delivery of nicotinic agonists evokes dose dependent nocifensive behavior and cardiovascular responses. Previous studies suggested that these effects may be attenuated by the loss of substance P positive (sP(+)) primary afferents. To further characterize these cell systems, we examined the effect of selectively destroying neurokinin 1 receptor bearing (NK1-r(+)) dorsal horn neurons on IT nicotinic agonist evoked responses. ⋯ These results indicate subunit-specific relationships between the NK1-r and nicotinic receptor systems. The loss of nocifensive activity after destruction of the NK1-r bearing cells in spite of the persistence of nicotinic subunits on other cells, emphasizes the importance of the superficial marginal neuron in mediating these nicotinic effects. Further, the exaggerated cardiovascular responses to cytisine following loss of NK1-r bearing cells suggest the presence of a nicotinic receptor-mediated stimulation of inhibitory circuits at the spinal level.
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Tramadol is an atypical analgesic with a unique dual mechanism of action. It acts on monoamine transporters to inhibit reuptake of noradrenaline (NA) and serotonin (5-HT), and consequent upon metabolism, displays potent agonist activity at micro-opioid receptors. Here, we present data for the novel compound NS7051, which was shown to have sub-micromolar affinity (Ki=0.034microM) for micro-opioid receptors and inhibited reuptake of 5-HT, NA and DA (IC(50)=4.2, 3.3 and 3.5microM in cortex, hippocampus and striatum respectively). ⋯ No ataxia was observed at antiallodynic doses giving therapeutic indices of 19 and 3 for NS7051 and tramadol. The combined opioid receptor agonism and monoamine reuptake inhibitory properties of NS7051 inferred from behavioural studies appear to contribute to its well tolerated antinociceptive profile in rats. However, unlike tramadol this did not correlate with the ability to increase hippocampal monoamine levels measured by microdialysis in anesthetised rats.