The Journal of neuroscience : the official journal of the Society for Neuroscience
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Comparative Study
Reduced expression of A-type potassium channels in primary sensory neurons induces mechanical hypersensitivity.
A-type K+ channels (A-channels) are crucial in controlling neuronal excitability, and their downregulation in pain-sensing neurons may increase pain sensation. To test this hypothesis, we first characterized the expression of two A-channels, Kv3.4 and Kv4.3, in rat dorsal root ganglion (DRG) neurons. Kv3.4 was expressed mainly in the nociceptive DRG neurons, in their somata, axons, and nerve terminals innervating the dorsal horn of spinal cord. ⋯ In a neuropathic pain model induced by spinal nerve ligation in rats, the protein levels of Kv3.4 and Kv4.3 in the DRG neurons were greatly reduced. After Kv3.4 or Kv4.3 expression in lumbar DRG neurons was suppressed by intrathecal injections of antisense oligodeoxynucleotides, mechanical but not thermal hypersensitivity developed. Together, our data suggest that reduced expression of A-channels in pain-sensing neurons may induce mechanical hypersensitivity, a major symptom of neuropathic pain.
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Comparative Study
Decreased central mu-opioid receptor availability in fibromyalgia.
The underlying neurophysiology of acute pain is fairly well characterized, whereas the central mechanisms operative in chronic pain states are less well understood. Fibromyalgia (FM), a common chronic pain condition characterized by widespread pain, is thought to originate largely from altered central neurotransmission. We compare a sample of 17 FM patients and 17 age- and sex-matched healthy controls, using mu-opioid receptor (MOR) positron emission tomography. ⋯ MOR BP in the accumbens of FM patients was negatively correlated with affective pain ratings. Moreover, MOR BP throughout the cingulate and the striatum was also negatively correlated with the relative amount of affective pain (McGill, affective score/sensory score) within these patients. These findings indicate altered endogenous opioid analgesic activity in FM and suggest a possible reason for why exogenous opiates appear to have reduced efficacy in this population.
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Comparative Study
The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons.
Itch is an everyday sensation, but when associated with disease or infection it can be chronic and debilitating. Several forms of itch can be blocked using antihistamines, but others cannot and these constitute an important clinical problem. Little information is available on the mechanisms underlying itch that is produced by nonhistaminergic mechanisms. ⋯ Histamine or cowhage responsive STT neurons were found in both the marginal zone and the deep dorsal horn and were classified as high threshold and wide dynamic range. Unexpectedly, histamine and cowhage never activated the same cell. Our results demonstrate that the spinothalamic tract contains mutually exclusive populations of neurons responsive to histamine or the nonhistaminergic itch-producing agent cowhage.
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Comparative Study
Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression.
NMDA receptor (NMDAR) activation is required for many forms of learning and memory as well as sensory system receptive field plasticity, yet the relative contribution of presynaptic and postsynaptic NMDARs over cortical development remains unknown. Here we demonstrate a rapid developmental loss of functional presynaptic NMDARs in the neocortex. Presynaptic NMDARs enhance neurotransmitter release at synapses onto visual cortex pyramidal cells in young mice [before postnatal day 20 (P20)], but they have no apparent effect after the onset of the critical period for receptive field plasticity (>P23). ⋯ Coincident with the observed loss of presynaptic NMDAR function, there is an abrupt change in the mechanisms of timing-dependent long-term depression (tLTD). Induction of tLTD before the onset of the critical period requires activation of presynaptic but not postsynaptic NMDARs, whereas the induction of tLTD in older mice requires activation of postsynaptic NMDARs. By demonstrating that both presynaptic and postsynaptic NMDARs contribute to the induction of synaptic plasticity and that their relative roles shift over development, our findings define a novel, and perhaps general, property of synaptic plasticity in emerging cortical circuits.
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The subthalamic nucleus (STN) plays a key role in the pathophysiology of Parkinson's disease. The modulation of the STN by norepinephrine, however, is unknown. The present study aims at characterizing the effects of systemic administration of noradrenergic agents on locomotor activity and on in vivo extracellularly recorded STN neuronal activity in intact and 6-hydroxydopamine (6-OHDA)-lesioned rats. ⋯ We further demonstrate that those systemic effects are supported, at least in part, by a direct modulation of STN neuronal activity, using patch-clamp recordings of STN neurons in brain slices. These findings support the premise that hypokinesia is associated with an increased STN neuronal activity, and that improvements of parkinsonian motor abnormalities are associated with a decrease in STN activity. Our data challenge assumptions about the role of alpha1-AR and alpha2-AR in the regulation of STN neurons in both intact and 6-OHDA-lesioned rats and further ground the rationale for using alpha2-AR noradrenergic antagonists in Parkinson's disease, albeit via an unexpected mechanism.