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J N Wood

Publications and source records attributed to J N Wood.

At least 19 recordsLinked to original sources
PubMed2007

Ion channels in analgesia research.

The distribution of ion channels in neurons associated with pain pathways is becoming better understood. In particular, we now have insights into the molecular nature of the channels that are activated by tissue-damaging stimuli, as well as the mechanisms by which voltage-gated channels alter the sensitivity of peripheral neurons to change pain thresholds. This chapter details the evidence that individual channels may be associated with particular pain states, and describes genetic approaches to test the possible utility of targeting individual channels to treat pain.

Analgesics↗
PubMed2006

muO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits.

The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na(v)1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that muO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for Na(v)1.8 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of Na(v)1.8 but not Na(v)1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human Na(v)1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward Na(v)1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

Animals↗
PubMed2004

Recent advances in understanding molecular mechanisms of primary afferent activation.

Thermal, mechanical, and chemical stimuli depolarise specialised damage sensing neurons to initiate electrical signals that may ultimately result in a sensation of pain. Over the past decade many of the receptors that transduce these signals have been identified by molecular cloning. In the absence of specific blockers, null mutant mice have proved valuable in exploring the function of these specialised receptors. As well as the mechanisms of signal transduction, the setting of thresholds for excitation and the transmission of electrical signals have also been the focus of intense interest. In vitro studies of dorsal root ganglion sensory neurons have thus facilitated rapid advances in our understanding of the biology of nociceptors. However, the specific properties of visceral afferents are poorly defined, and useful animal models of visceral pain are only now being developed. Visceral neuron receptor subtypes and the consequences of their activation in terms of pain perception and behaviour are thus subjects that still demand a major research effort.

Animals↗
PubMed2003

Category-specific representations of social and nonsocial knowledge in the human prefrontal cortex.

Complex social behavior and the relatively large size of the prefrontal cortex are arguably two of the characteristics that distinguish humans from other animals. Grafman presented a framework concerning how the prefrontal cortex (PFC) controls complex behavior using stored structured event complexes (SECs). We report behavioral and imaging data from a modified go/no-go paradigm in which subjects had to classify words (semantic) and phrases (SEC) according to category. In experimental trials, subjects classified items according to social or nonsocial activity; in control trials, they classified items according to font. Subjects were faster to classify social than nonsocial semantic items, with the reverse pattern evident for the social and nonsocial SEC items. In addition, the conditions were associated with different patterns of PFC activation. These results suggest that there are different psychological and neural substrates for social and nonsocial semantic and SEC representations.

Activities of Daily Living↗
PubMed2001

A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain.

The tetrodotoxin-resistant voltage-gated sodium channel Nav 1.8 is expressed only in nociceptive sensory neurons. This channel has been proposed to contribute significantly to the sensitization of primary sensory neurons after injury. We have studied the nociceptive behaviours of mice carrying a null mutation in the Nav 1.8 gene (Nav 1.8 -/-) in models of peripheral inflammation as well as a model of neuropathic pain. The results from the present studies reveal that Nav 1.8 is a necessary mediator of NGF-induced thermal hyperalgesia but is not essential for PGE2-evoked hypersensitivity. Neuropathic pain behaviours were unchanged in Nav 1.8 -/- mice indicating that this channel is not involved in the alteration of sensory thresholds following peripheral nerve injury.

Animals↗
PubMed2001

Flanking regulatory sequences of the locus encoding the murine GDNF receptor, c-ret, directs lac Z (beta-galactosidase) expression in developing somatosensory system.

RET forms the catalytic component within the receptor complex that transmits signals from the GDNF family of neurotrophic factors. To study the mechanisms regulating the cell-type specific expression of this gene, we have cloned and characterised the murine c-ret locus. A cosmid contig comprising approximately 60 kb of the mouse genome encompassing the entire structural gene and flanking sequences have been isolated and the transcription initiation site identified and promoter characterised. The murine c-ret promoter lacks a TATA initiation motif and has GC enriched DNA sequences reminiscent of CpG islands. Analysis of transgenic mice lines bearing the Lac Z (beta-galactosidase) reporter gene under the control of 5' flanking sequences show modularity in the organisation of cis-regulatory domains within the locus. Cloned 5' flanking sequences comprise a distal regulatory domain directing Lac Z expression at the primitive streak, lateral mesoderm and facial ganglia and a proximal sensory neurones specific regulatory domain inducing Lac Z expression primarily within the developing somatosensory system. The spatial and temporal progression of transgene expression precisely recapitulates endogenous gene expression in developing sensory ganglia including its induction in postnatal Isolectin B4 binding nociceptive neurones.

Animals↗
PubMed2001

Involvement of Na+ channels in pain pathways.

Voltage-dependent Na+ channels in sensory nerves contribute to the control of membrane excitability and underlie action potential generation. Na+ channel subtypes exhibit a neurone-specific and developmentally regulated pattern of expression, and changes in both channel expression and function are caused by disease. Recent evidence implicates specific roles for Na+ channel subtypes Na(v)1.3 and Na(v)1.8 in pain states that are associated with nerve injury and inflammation, respectively. Insight into the role of Na(v)1.8 in pain pathways has been gained by the generation of a null mutant. Although drugs discriminate poorly between subtypes, the molecular diversity of channels and subtype-specific modulation might provide opportunities to target pain pathways selectively.

Action Potentials↗
PubMed2001

Neurobiology.

Explore the source record for details and available documents.

Journal Article↗
PubMed2001

Neurobiology.

Explore the source record for details and available documents.

Animals↗
PubMed2001

Voltage-gated sodium channels.

Increased knowledge of the molecular diversity of sodium channel alpha- and beta-subunits, and their distribution of expression have been highlights of the past year. The development of subtype-specific channel blockers remains elusive, but the discovery of selective inhibitors such as mu-conotoxins promises useful antagonists in the near future.

Animals↗
PubMed2000

Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors.

ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli.

Adenosine Triphosphate↗
PubMed2000

Potent analgesic effects of GDNF in neuropathic pain states.

Neuropathic pain arises as a debilitating consequence of nerve injury. The etiology of such pain is poorly understood, and existing treatment is largely ineffective. We demonstrate here that glial cell line-derived neurotrophic factor (GDNF) both prevented and reversed sensory abnormalities that developed in neuropathic pain models, without affecting pain-related behavior in normal animals. GDNF reduces ectopic discharges within sensory neurons after nerve injury. This may arise as a consequence of the reversal by GDNF of the injury-induced plasticity of several sodium channel subunits. Together these findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.

Action Potentials↗
PubMed2000

A new member of the acid-sensing ion channel family.

Acid-sensing ion channels (ASICs) are members of the epithelial sodium channel (ENaC)-degenerin family of two-pass transmembrane segment protein subunits which form multimeric cation channels. Members of the ENaC-degenerin family are gated by stimuli as diverse as protons, peptides and mechanical distension. Here we describe a new member of the family, SPASIC or ASIC 4 (spinal cord ASIC) which is expressed throughout the central nervous system in an overlapping population of neurons that also express the ASIC subunit MDEG2. ASIC-4 which shows 44% identify with ASIC is developmentally regulated and expressed in a subset of sensory neurons as well as in the CNS. However, despite the strong homology with ASIC, the ASIC-4 transcript does not encode a proton gated cation channel.

Acid Sensing Ion Channels↗
PubMed2000

ATP, P2X receptors and pain pathways.

A role for ATP in nociception and pain induction was proposed on the basis of human psychophysical experiments shortly after the formulation of the purinergic hypothesis. Following the pharmacological definition of distinct P2X and P2Y purinergic receptor subtypes by Burnstock and his collaborators, molecular cloning studies have identified the gene products that underlie the effects of ATP on peripheral sensory neurons. One particular receptor, P2X(3), is of particular interest in the context of pain pathways, because it is relatively selectively expressed at high levels by nociceptive sensory neurons. Evidence that this receptor may play a role in the excitation of sensory neurons has recently been complemented by studies that suggest an additional presynaptic role in the regulation of glutamate release from primary afferent neurons in the dorsal horn of the spinal cord. In this brief review, we discuss the present state of knowledge of the role of ATP in pain induction through its action on peripheral P2X receptors.

Adenosine Triphosphate↗
PubMed2000

Molecules that specify modality: mechanisms of nociception.

Damage-sensing neurons express a unique cohort of genes encoding channels and receptors that play a role in nociception. However, there are redundant pathways involved in, for example, inflammatory pain and many channels and receptors have additional physiologic roles unrelated to nociception. Thus, it is impossible to ascribe a particular sensory modality to the expressions of a single molecular entity. Despite this, the relatively selective expression of a number of channels and receptors in nociceptive neurons provide potentially interesting analgesic drug targets that can be examined through the generation of knockout mice.

Journal Article↗
PubMed2000

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. II. Genetic approaches to pain therapy.

New analgesic drugs are necessary because a number of pain states are untreatable. Genetic approaches to the identification of analgesic drug targets include mapping genes involved in human pain perception (e.g., trkA involved in hereditary neuropathies), identifying regulators of sensory neuron function in simple multicellular organisms and then investigating the activity of their mammalian homologs (e.g., POU domain transcription factors that specify sensory cell fate), as well as difference, expression, and homology cloning of receptors, ion channels, and transcription factors present in sensory neurons. After target validation through the construction of null mutant mice, high-throughput cell-based screens can be used to identify potential drug candidates. As a result of these approaches, a number of receptors and ion channels present in sensory neurons such as voltage-gated sodium channels [sensory neuron specific (SNS) and Na channel novel] and ATP-gated (P2X3), capsaicin-gated [vanilloid receptor 1(VR1)], and proton-gated [acid-sensing ion channel (ASIC)] channels are now under investigation as potential new analgesic drug targets.

Animals↗