Neuroscience
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Administration of ABT-594, a potent agonist for nicotinic acetylcholine receptors with selectivity for the alpha4beta2 receptor subtype, is known to modulate a diverse array of behaviors including those associated with nociception, anxiety and motor function. In this study, we sought to gain insight into the neural actions of ABT-594, in vivo, by conducting functional magnetic resonance imaging in awake and anesthetized rats. Using T(2)*-weighted gradient echo imaging and an ultrasmall superparamagnetic iron oxide contrast agent, functional imaging was conducted on a 4.7 T magnet to measure changes in relative cerebral blood volume. ⋯ Both increases and decreases in relative cerebral blood volume were blocked by pretreatment with the noncompetitive nicotinic acetylcholine receptor antagonist, mecamylamine (5 micromol/kg, i.p.) in awake rats. Administration of ABT-594 (0.1 micromol/kg, i.v.) to alpha-chloralose-anesthetized rats did not significantly alter relative cerebral blood volume in any brain region suggesting an anesthetic-related interference with the effects of ABT-594. The neural regions affected by administration of ABT-594 corresponded well to the known pre-clinical behavioral profile for this compound, and demonstrate the utility of using functional magnetic resonance imaging in awake animals to study pharmacological action.
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Neuropeptide W-23 and neuropeptide B are each an endogenous ligand of GPR7. GPR7 mRNA has been detected in regions of the cortex, the hippocampus, the hypothalamus and the spinal cord in the rat. GPR7 receptor has structural features in common with both opioid and somatostatin receptors. ⋯ The effect of intrathecal administration of either 10 microg of neuropeptide W-23 or 10 microg of neuropeptide B was not antagonized by i.p. injection of 1 mg/kg of naloxone. Immunohistochemical examination revealed that neuropeptide W-23 was expressed mainly in the small- to medium-sized neuronal profiles in the dorsal root ganglion and that partial sciatic nerve injury decreased the percentage of neuropeptide W-23-like immunoreactivity positive neuronal profiles that were labeled by IB4. These data suggest that neuropeptide W-23 is involved in the nociceptive transmission in spinal cord and that both spinally-applied neuropeptide W-23 and spinally-applied neuropeptide B produce anti-allodynic effects in the partial sciatic nerve ligation model in rat.
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It is well known that following peripheral nerve injury, there are numerous changes in neurotransmitter and neuropeptide expression in the superficial dorsal horn, the dorsal root ganglion and the periphery. Of particular interest are the relative contributions of two sub-types of unmyelinated C-fibers in the initiation and maintenance of chronic pain, the peptidergic, and the non-peptidergic. Evidence gathered in recent years has led researchers to believe that the non-peptidergic nociceptive primary afferents are functionally distinct from their peptidergic counterpart. ⋯ As the central boutons of type Ia represent varicosities from the fibers which bind IB4, the ultrastructural changes confirmed that there was a bona fide transient loss of varicosities, not simply a loss of IB4 binding. These data indicate that, in this animal model, morphological changes in the nociceptive C-fiber input of the rat dorsal horn are restricted to the non-peptidergic sub-population and are transient in nature. Furthermore, such changes do not correlate with the time-course of the allodynia.
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Mutations in the SOD1 gene are associated with familial amyotrophic lateral sclerosis. The mechanisms by which these mutations lead to cell loss within the spinal cord ventral horns are unknown. In the present report we used the G93A transgenic mouse model of amyotrophic lateral sclerosis to develop and characterize an in vitro tool for the investigation of subtle alterations of spinal tissue prior to frank neuronal degeneration. ⋯ However, a significantly different ratio between inhibitory and excitatory synapses was present in G93A cultures, when compared with wild type ones, suggesting the expression of subtle synaptic dysfunction in G93A cultured tissue. When compared with controls, G93A motoneurons exhibited increased vulnerability to AMPA glutamate receptor-mediated excitotoxic stress prior to clear disease appearance. This in vitro disease model may thus represent a valuable tool to test early mechanisms contributing to motoneuron degeneration and potential therapeutic molecular interventions.
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The amygdala plays a key role in emotional processing and anxiety-related physiological and behavioral responses. Previous studies have shown that injections of the anxiety-related neuropeptide corticotropin-releasing factor or the related neuropeptide urocortin 1 into the region of the basolateral amygdaloid nucleus induce anxiety-like behavior in several behavioral paradigms. Brainstem serotonergic systems in the dorsal raphe nucleus and median raphe nucleus may be part of a distributed neural system that, together with the basolateral amygdala, regulates acute and chronic anxiety states. ⋯ These behavioral effects were associated with increases in c-Fos expression within brainstem serotonergic neurons. In home cage rats and rats exposed to the social interaction test, urocortin 1 treatment increased the number of c-Fos-immunoreactive serotonergic neurons within subdivisions of both the dorsal raphe nucleus and median raphe nucleus. These results are consistent with the hypothesis that the basolateral amygdala and serotonergic neurons within the midbrain raphe complex are part of an integrated neural system modulating anxiety state.