Neuropharmacology
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GABA(B) receptor antagonists have been shown to have antidepressant-like properties in animal models and thus, could represent a novel approach for the treatment of depression. The neurobiological mechanisms underlying these effects are currently unknown. Adult hippocampal neurogenesis (the birth of new neurons) is thought to play a role in antidepressant drug action. ⋯ This topographical segregation concurs with the hypothesis that the ventral hippocampus is primarily involved in the regulation of stress and emotionality. Taken together, our data suggest that increased hippocampal cell proliferation is a plausible mechanism for the antidepressant-like effects of GABA(B) receptor antagonists following chronic but not acute treatments. Moreover, altered behavioural effects in the FST does not correlate with changes in neurogenesis.
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We investigated whether the RhoA/ROCK pathway was involved in the effect of erythropoietin (EPO) to promote retinal ganglion cells (RGCs) axonal regeneration in a rat optic nerve crush (ONC) model. We demonstrated that both EPO and ROCK inhibitor Y-27632 significantly enhanced RGCs survival and axon regeneration in vivo, and the effects of these agents were additive. ⋯ Down-regulation of active-RhoA, ROCK-1, and ROCK-2 expression by EPO coincided with the appearance of larger numbers of regenerating axons. In conclusion, the RhoA/ROCK signaling pathway was involved in the EPO effect to promote RGCs axon regeneration after ONC.
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Among receptors mediating serotonin actions in pain control, the 5-HT(7)R is of special interest because it is expressed by primary afferent fibers and intrinsic GABAergic and opioidergic interneurons within the spinal dorsal horn. Herein, we investigated whether GABA and/or opioids contribute to 5-HT(7)R-mediated control of neuropathic pain caused by nerve ligation. Acute administration of 5-HT(7)R agonists (AS-19, MSD-5a, E-55888) was found to markedly reduce mechanical and thermal hyperalgesia in rats with unilateral constriction injury to the sciatic nerve (CCI-SN). ⋯ When injected intrathecally (i.t.), bicuculline (3 μg i.t.), but neither phaclofen (5 μg i.t.) nor naloxone (10 μg i.t.), significantly reduced the anti-hyperalgesic effects of 5-HT(7)R activation (E-55888, 10 mg/kg s.c.) in CCI-SN rats. These data support the idea that 5-HT(7)R-mediated inhibitory control of neuropathic pain is underlain by excitation of GABAergic interneurons within the dorsal horn. In addition, 5-HT(7)R activation-induced c-Fos increase in the nucleus tractus solitarius and the parabrachial area suggests that supraspinal mechanisms might also be involved.
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Mice lacking the NK(1) receptor (NK(1)R-/- mice) and selective, high-affinity, non-peptide, NK(1), NK(2) and NK(3) receptor antagonists were used to identify the tachykinin receptor subtype(s) mediating the central responses induced by neurokinin A (NKA). The peptides, substance P (SP), NKA and senktide and the antagonists were injected intracerebroventricularly (ICV) through an implanted cannula. NKA (50 pmol) was as potent as SP (50 pmol) in inducing grooming behaviour (face washing and hind limb grooming) in wild-type mice, but both peptides failed to induce behavioural responses in NK(1)R-/- mice. ⋯ The NK(3) receptor antagonist, SR 142801, inhibited behaviours induced by the NK(3) receptor agonist, senktide, but did not alter behavioural responses to either SP or NKA in wild-type mice. The present findings demonstrate that central biological actions of SP and senktide are mediated by activation of NK(1) and NK(3) receptors, respectively. Our results also indicate that NK(1) receptors are essential for generating central actions induced by NKA, which are most probably mediated by a cross-talk between the NK(1) and NK(2) receptors.
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Comparative Study
AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies.
Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). ⋯ AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent of these antagonists effects may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.