Neuroscience
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Although the distribution of calcitonin gene-related peptide has been extensively studied in the spinal cord, little is known about the precise subcellular localization of receptors for calcitonin gene-related peptide. The present study was undertaken to localize calcitonin gene-related peptide receptors in both the dorsal and ventral horns of the rat spinal cord. Immunocytochemical localization with specific monoclonal antibodies was performed at the light and electron microscopic levels. ⋯ Motoneurons, on the other hand, were contacted by axonal terminals with presynaptic calcitonin gene-related peptide receptors. These data suggest that (i) dorsal horn neurons are capable of direct primary afferent, calcitonin gene-related peptide receptor-mediated interactions and (ii) neuronal terminals contacting motor horn cells can be influenced through presynaptic paracrine-like calcitonin gene-related peptide receptor-mediated interactions. Thus, calcitonin gene-related peptide can have multiple modulatory effects on spinal cord neurons through site-specific receptors.
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Sprouting of the mossy fiber axons of the dentate granule cells is a structural neuronal plasticity found in the mature brain of epileptic humans and experimental animals. Mossy fiber sprouting typically arises in experimental animals after repeated seizures and may contribute to the hyperexcitability of the epileptic brain. Investigation of the molecular triggers and spatial cues involved in mossy fiber sprouting has been hampered by the lack of an optimal in vitro model for studying this rearrangement. ⋯ The cellular and molecular determinants required for kainic acid-induced cell death and subsequent mossy fiber reorganization thus appear to be intrinsic to the hippocampal slice preparation, and are preserved in culture. Given the ease with which functional inhibitors or pharmacological agents may be utilized in this system, slice cultures may provide a powerful model in which to study the molecular components involved in triggering mossy fiber outgrowth and underlying its laminar specificity. Elucidation of these molecular pathways will likely have both specific utility in clarifying the functional consequences of mossy fiber sprouting, as well as general utility in understanding of synaptic reorganization in the mature central nervous system.
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A few hours after peripheral axons of cutaneous afferent neurons have been transected, some of their novel endings become excitable by physical or chemical stimuli. It has been assumed that these axon endings preferentially respond to those stimuli which have excited their previous receptive endings. We studied the prevalence of sensory properties among 784 unmyelinated sural nerve fibres which had been axotomized 2-24 h before, by applying mechanical and thermal forces to the nerve lesion site. ⋯ The distribution of sensory properties among acutely axotomized sural nerve C-fibres is therefore largely similar to the recently published distribution of receptor types among intact sural nerve C-fibre afferents. Thus, the hypothesis that responses of axotomized afferent fibres reflect their original receptive properties is corroborated. Knowledge of underlying transduction mechanisms may lead to specific pharmacological tools for suppression of ectopic discharges in unmyelinated axotomized afferents, which probably contribute to neuropathic pain states.
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Repeated dopamine agonist administration to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway potentiates behavioral and neuronal activation in response to subsequent dopamine agonist treatment. This response sensitization has been termed "priming" or "reverse-tolerance". Our prior work has shown that three pretreatment injections of the mixed D1/D2 agonist apomorphine (0.5 mg/kg) into 6-hydroxydopamine-lesioned rats permits a previously inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to induce robust contralateral rotation and striatal Fos expression in striatoentopeduncular "direct" pathway neurons. ⋯ These responses are equivalent to the changes observed in apomorphine-primed 6-hydroxydopamine-lesioned rats challenged with D2 agonist. In contrast, D2 agonist priming was not associated with D2-mediated induction of striatal immediate-early gene expression even though priming of D2-mediated rotational behavior was not different from that observed following priming with apomorphine or D1 agonist. Therefore, while priming-induced alterations in D2-mediated immediate early gene expression in the "direct" striatal output pathway may contribute to the enhanced motor behavior observed, such changes in striatal gene expression do not appear to be required for this potentiated motor response in dopamine-depleted rats.
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There appear to be different relationships between mu-opioid receptor densities and the acute and neuroadaptive mu-opioid agonist-induced responses of the multiple opioid neuronal systems, including important pons/medulla circuits. The recent success in creating mu-opioid receptor knockout mice allows studies of mu-opioid agonist-induced pharmacological and physiological effects in animals that express no, one or two copies of the mu-opioid receptor gene. We now report that the binding of mu-opioid receptor ligand, [3H][D-Ala2,NHPhe4,Gly-ol]enkephalin to membrane preparations of the pons/medulla was reduced by half in heterozygous mu-opioid receptor knockout mice and eliminated in homozygous mu-opioid receptor knockout mice. ⋯ These antinociceptive actions were significantly reduced in heterozygous mu-opioid receptor knockout mice, and virtually abolished in homozygous knockout mice. The mu-opioid receptors are the principal molecular targets for endomorphin-induced G-protein activation in the pons/medulla and the antinociception caused by the intracerebroventricular administration of mu-opioid agonists. These data support the notion that there are limited physiological mu-opioid receptor reserves for inducing G-protein activation in the pons/medulla and for the nociceptive modulation induced by the central administration of endomorphin-1 and -2.