Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage - a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states.

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It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain-derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long-term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin-1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin-1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin-1 receptor knockout mice. Neurogenesis can be increased in wild-type but not neurokinin-1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain-derived neurotrophic factor are also two-fold higher in neurokinin-1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus-dependent learning and memory but found no clear enhancement in neurokinin-1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain-derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain-derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy.

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The behaviour of neurokinin-1-receptor gene knockout (NK1R-/-) mice, which lack functional, substance P-preferring receptors, resembles that of NK1R+/+ mice treated with an antidepressant. Because all antidepressants increase central monoamine transmission, we have investigated whether noradrenergic transmission is increased in NK1R-/- mice and, if so, whether this could influence their behaviour. In anaesthetized subjects, the concentration of extracellular noradrenaline in NK1R-/- mice was two-fourfold greater than in NK1R+/+ mice. Systemic administration of the alpha2-adrenoceptor antagonist, 2-(2,3-dihydro-2-methoxy-1,4-benzodioxan-2-yl)-4,5-dihydro-1H-imidazoline (RX 821002), in anaesthetized or freely moving animals increased extracellular noradrenaline in NK1R+/+ mice only. This suggests that the function of alpha2a-autoreceptors, which modulate noradrenergic transmission, is impaired in NK1R-/- mice. Consistent with this, [35S]GTPgammaS binding to activated alpha2a-adrenoceptors was lower (-70%) in the locus coeruleus, but not the frontal cortex, of NK1R-/- mice compared with their NK1R+/+ counterparts. RX 821002-pretreatment, followed by retrodialysis of the noradrenaline reuptake inhibitor, desipramine, into the frontal cortex of anaesthetized mice increased extracellular noradrenaline to the same extent in the two genotypes. Western blots confirmed that there was no difference in the amount of noradrenaline transporter protein in NK1R-/- and NK1R+/+ mice. Finally, the effects of RX 821002 on certain behaviours in a light/dark exploration box were blunted in NK1R-/- mice, but there was no consistent effect on anxiety-like behaviour in the two genotypes. It is concluded that the greater basal efflux of noradrenaline in NK1R-/- mice is explained by increased transmitter release, coupled with desensitization of somatodendritic alpha2a-adrenoceptors. These changes could contribute to the difference in the behavioural phenotypes.

From electronic structure calculations, we find that carriers injected into dangling-bond atomic wires on the Si(001) surface will self-trap to form localised polaron states. The self-trapping distortion takes the form of a local suppression of the buckling of the dimers in the wire, and is qualitatively different for the electron and hole polarons. This result points to the importance of polaronic effects in understanding electronic motion in such nanostructures.Comment: LaTeX with APS RevTeX macros; 14 pages including 4 figures in EPS forma

The density of the Imidazoline₂ binding site (I₂BS) has been shown to change in psychiatric conditions such as depression and addiction, along with neurodegenerative disorders such as Alzheimer's disease and Huntington's chorea. The presence of I₂BS on glial cells and the possibility that they may in some way regulate glial fibrillary acidic protein has led to increased interest into the role of I₂BS and I₂BS ligands in conditions characterized by marked gliosis. In addition, it has been suggested that I₂BS may be a marker for human glioblastomas. Therefore, the development of a positron emission tomography (PET) radioligand for the I₂BS would be of major benefit in our understanding of these conditions. We now report the successful synthesis and initial pharmacological evaluation of potential PET radioligands for the I₂BS as well as the tritiation and characterization of the most favorable of the series, BU99008 (6), both in vitro and ex vivo in rat. The series as a whole demonstrated excellent affinity and selectivity for the I₂BS, with BU99008 (6) selected as the lead candidate to be taken forward for in vivo assessment. BU99008 (6) showed very good affinity for the I₂BS (K(i) of 1.4 nM; K(d) = 1.3 nM), good selectivity compared with the α₂ -adrenoceptor (909-fold). In addition, following peripheral administration, [³H]BU99008 demonstrated a heterogenous uptake into the rat brain consistent with the known distribution of the I₂BS in vivo. This, and the amenability of BU99008 (6) to radiolabeling with a positron-emitting radioisotope, indicates its potential as a PET radioligand for imaging the I₂BS in vivo.

A large number of cytokines and growth factors support the development and subsequent maintenance of postnatal motor neurons. RegIII␤, also known as Reg2 in rat and HIP/PAP1 in humans, is a member of a family of growth factors found in many areas of the body and previously shown to play an important role in both the development and regeneration of subsets of motor neurons. It has been suggested that RegIII␤ expressed by motor neurons is both an obligatory intermediate in the downstream signaling of the leukemia inhibitory factor/ciliary neurotrophic factor (CNTF) family of cytokines, maintaining the integrity of motor neurons during development, as well as a powerful influence on Schwann cell growth during regeneration of the peripheral nerve. Here we report that in mice with a deletion of the RegIII␤ gene, motor neuron survival was unaffected up to 28 weeks after birth. However, there was no CNTF-mediated rescue of neonatal facial motor neurons after axotomy in KO animals when compared with wild-type. In mice, RegIII␤ positive motor neurons are concentrated in cranial motor nuclei that are involved in the patterning of swallowing and suckling. We found that suckling was impaired in RegIII␤ KO mice and correlated this with a significant delay in myelination of the hypoglossal nerve. In summary, we propose that RegIII␤ has an important role to play in the developmental fine-tuning of neonatal motor behaviors mediating the response to peripherally derived cytokines and growth factors and regulating the myelination of motor axons.Schwann cells ͉ suckling ͉ hypoglossal nerve ͉ LIF