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Biomedical subjects

C J Woolf

Publications and source records attributed to C J Woolf.

At least 37 records · Page 2Linked to original sources
PubMed2000

Contribution of central sensitisation to the development of non-cardiac chest pain.

BACKGROUND: Non-cardiac chest pain mimics angina pectoris but generally originates from the oesophagus. Visceral hypersensitivity may contribute, but its neurophysiological basis is unclear. We investigated whether central sensitisation, an activity-dependent amplification of sensory transfer in the central nervous system, underlies visceral pain hypersensitivity and non-cardiac chest pain. METHODS: We studied 19 healthy volunteers and seven patients with non-cardiac chest pain. Acid was infused into the lower oesophagus. Sensory responses to electrical stimulation were monitored within the acid-exposed lower oesophagus, the non-exposed upper oesophagus, and the cutaneous area of pain referral, before and after the infusion. FINDINGS: In healthy volunteers, acid infusion into the lower oesophagus lowered the pain threshold in the upper oesophagus (mean decrease 18.2% [95% CI 10.4 to 26.0]; p=0.01) and on the chest wall (24.5% [10.2 to 38.7]; p=0.01). Patients with non-cardiac chest pain had a lower resting oesophageal pain threshold than healthy controls (45 [30 to 58] vs 64 [49 to 81] mA; p=0.04). In response to acid infusion, their pain threshold in the upper oesophagus fell further and for longer (mean fall in area under threshold/time curve 26.7 [11.0 to 42.3] vs 5.8 [2.8 to 8.8] units; p=0.04). INTERPRETATION: The finding of secondary viscerovisceral and viscerosomatic pain hypersensitivity suggests that central sensitisation may contribute to visceral pain disorders. The prolonged visceral pain hypersensitivity in patients with non-cardiac chest pain suggests a central enhancement of sensory transfer. New therapeutic opportunities are therefore possible.

Adult↗
PubMed2000

Resection of sciatic nerve re-triggers central sprouting of A-fibre primary afferents in the rat.

We have investigated whether nerve injury or target deprivation is responsible for the injury induced central sprouting of A-fibres. Cholera toxin B subunit conjugated horseradish peroxidase was used to trace the termination of A-fibre primary afferents. Transection of the sciatic nerve induces central sprouting of sciatic myelinated A-fibre primary afferents into the spinal dorsal horn lamina II, which normally is the termination site of unmyelinated C-fibre primary afferents. The sprouting A-fibre terminals withdrew from lamina II after six to eight months. A second cut to the previously sectioned and ligated sciatic nerve re-triggered the central sprouting of A-fibre primary afferents into the spinal dorsal horn lamina II, suggesting that nerve injury per se rather than the deprivation of target tissues is the cause of central sprouting of A-fibre primary afferents.

Animals↗
PubMed2000

Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve.

The present study deals with changes in numbers and sizes of primary afferent neurons (dorsal root ganglion [DRG] cells) after sciatic nerve transection. We find that this lesion in adult rats leads to death of some DRG cells by 8 weeks and 37% by 32 weeks after the lesion. The loss of cells appears earlier in and is more severe in B-cells (small, dark cells with unmyelinated axons) than A-cells (large, light cells with myelinated axons). With regard to mean cell volumes, there is a tendency for both categories of DRG cells to be smaller, but except for isolated time points, these differences are not statistically significant. These findings differ from most earlier reports in that the cell loss takes place later than usually reported, that the loss is more severe for B-cells, and that neither A- or B-cells change size significantly. Accordingly, we conclude that sciatic nerve transection in adult rats leads to a slowly developing but relatively profound loss of primary afferent neurons that is more severe for B-cells. These results can serve as a basis for studies to determine the effectiveness of trophic or survival factors in avoiding axotomy induced cell death.

Animals↗
PubMed2000

Neuronal plasticity: increasing the gain in pain.

We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.

Animals↗
PubMed2000

Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2.

The differential distribution of two tetrodotoxin resistant (TTXr) voltage-gated sodium channels SNS (PN3) and SNS2 (NaN) in rat primary sensory neurons has been investigated. Both channels are sensory neuron specific with SNS2 restricted entirely to those small dorsal root ganglion (DRG) cells with unmyelinated axons (C-fibers). SNS, in contrast, is expressed both in small C-fiber DRG cells and in 10% of cells with myelinated axons (A-fibers). All SNS expressing A-fiber cells are Trk-A positive and many express the vanilloid-like receptor VRL1. About half of C-fiber DRG neurons express either SNS or SNS2, and in most, the channels are colocalized. SNS and SNS2 are found both in NGF-responsive and GDNF-responsive C-fibers and many of these cells also express the capsaicin receptor VR1. A very small proportion of small DRG cells express either only SNS or only SNS2. At least four different classes of A- and C-fiber DRG neurons exist, therefore, with respect to expression of these sodium channels.

Animals↗
PubMed2000

Pain.

Explore the source record for details and available documents.

Humans↗
PubMed2000

Trigeminal neuralgia: opportunities for research and treatment.

Trigeminal neuralgia was the focus of a recent workshop convened by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Dental and Craniofacial Research (NIDCR). The workshop brought together basic scientists, clinicians, epidemiologists, and patient advocates. New research directions for epidemiology, diagnosis and assessment, pain mechanisms, and treatment were identified. (The workshop was held in Rockville MD on September 14, 1999, with financial support from NINDS, NIDCR, the NIH Office of Rare Diseases, and the NIH Pain Research Consortium.)

Animals↗
PubMed2000

Pain: molecular mechanisms.

Our understanding of chronic inflammatory and neuropathic pain at the molecular and cellular level has developed at an extraordinary rate in recent years. Inflammatory, or neuropathic, neuronal plasticity describes the process by which the neurons involved in pain transmission are converted from a state of normosensitivity to one in which they are hypersensitive. Here we summarize current theories on somatosensory neuroplasticity in a molecular context, highlighting key receptors, ion channels, and signal molecules involved. We also suggest new possibilities for drug design, based on the rational targeting of these molecular players.

Journal Article↗
PubMed2000

Pain mechanisms and management: a central perspective.

Although pain is always intense and unpleasant, the capacity to experience this sensation is, under normal circumstances, fundamental to the preservation of bodily integrity. Clinically, however, after injury to peripheral tissue or directly to the nervous system, spontaneous and evoked pain manifest that serve no physiologic function, are crippling to patients, and are difficult to treat. Here, we review the specific role of the dorsal horn of the spinal cord in the mechanisms of nociceptive protective pain and the spinal plasticity that occurs after nerve and tissue injury. This spinal neuronal plasticity is shown to be a key contributor to pathologic pain hypersensitivity. The potential for the molecular mechanisms responsible for the spinal plasticity in revealing new targets for future treatment is also discussed.

Animals↗
PubMed2000

Silent NMDA receptor-mediated synapses are developmentally regulated in the dorsal horn of the rat spinal cord.

In vitro whole cell patch-clamp recording techniques were utilized to study silent pure-N-methyl-D-aspartate (NMDA) receptor-mediated synaptic responses in lamina II (substantia gelatinosa, SG) and lamina III of the spinal dorsal horn. To clarify whether these synapses are present in the adult and contribute to neuropathic pain, transverse lumbar spinal cord slices were prepared from neonatal, naive adult and adult sciatic nerve transected rats. In neonatal rats, pure-NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) were elicited in SG neurons either by focal intraspinal stimulation (n = 15 of 20 neurons) or focal stimulation of the dorsal root (n = 2 of 7 neurons). In contrast, in slices from naive adult rats, no silent pure-NMDA EPSCs were recorded in SG neurons following focal intraspinal stimulation (n = 27), and only one pure-NMDA EPSC was observed in lamina III (n = 23). Furthermore, in rats with chronic sciatic nerve transection, pure-NMDA EPSCs were elicited by focal intraspinal stimulation in only 2 of 45 SG neurons. Although a large increase in Abeta fiber evoked mixed alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptor-mediated synapses was detected after sciatic nerve injury, Abeta fiber-mediated pure-NMDA EPSCs were not evoked in SG neurons by dorsal root stimulation. Pure-NMDA receptor-mediated EPSCs are therefore a transient, developmentally regulated phenomenon, and, although they may have a role in synaptic refinement in the immature dorsal horn, they are unlikely to be involved in receptive field plasticity in the adult.

2-Amino-5-phosphonovalerate↗
PubMed1999

Semaphorin 3A growth cone collapse requires a sequence homologous to tarantula hanatoxin.

Axonal guidance is key to the formation of neuronal circuitry. Semaphorin 3A (Sema 3A; previously known as semaphorin III, semaphorin D, and collapsin-1), a secreted subtype of the semaphorin family, is an important axonal guidance molecule in vitro and in vivo. The molecular mechanisms of the repellent activity of semaphorins are, however, poorly understood. We have now found that the secreted semaphorins contain a short sequence of high homology to hanatoxin, a tarantula K(+) and Ca(2+) ion channel blocker. Point mutations in the hanatoxin-like sequence of Sema 3A reduce its capacity to repel embryonic dorsal root ganglion axons. Sema 3A growth cone collapse activity is inhibited by hanatoxin, general Ca(2+) channel blockers, a reduction in extracellular or intracellular Ca(2+), and a calmodulin inhibitor, but not by K(+) channel blockers. Our data support an important role for Ca(2+) in mediating the Sema 3A response and suggest that Sema 3A may produce its effects by causing the opening of Ca(2+) channels.

Amino Acid Sequence↗
PubMed1999

A role for HSP27 in sensory neuron survival.

Peripheral nerve injury in neonatal rats results in the death of the majority of the axotomized sensory neurons by 7 d after injury. In adult animals, however, all sensory neurons survive for at least 4 months after axotomy. How sensory neurons acquire the capacity to survive axonal injury is not known. Here we describe how the expression of the small heat shock protein 27 (HSP27) is correlated with neuronal survival after axotomy in vivo and after NGF withdrawal in vitro. The number of HSP27-immunoreactive neurons in the L4 DRG is low at birth and does not change significantly for 21 d after postnatal day 0 (P0) sciatic nerve axotomy. In contrast, in the adult all axotomized neurons begin to express HSP27. One week after P0 sciatic nerve section the total number of neurons in the L4 DRG is dramatically reduced, but all surviving axotomized neurons, as identified by c-jun immunoreactivity, are immunoreactive for HSP27. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling reveals that very few HSP27-expressing neurons are dying 48 hr after neonatal axotomy. In vitro, a similar correlation exists between HSP27 expression and survival; in P0 DRG cultures, neurons that express HSP27 preferentially survive NGF withdrawal. Finally, overexpression of human HSP27 in neonatal rat sensory and sympathetic neurons significantly increases survival after NGF withdrawal, with nearly twice as many neurons surviving at 48 hr. Together these results suggest that HSP27 in sensory neurons plays a role in promoting survival after axotomy or neurotrophin withdrawal.

Aging↗
PubMed1999

Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity.

Brain-derived neurotrophic factor (BDNF) is expressed in nociceptive sensory neurons and transported anterogradely to the dorsal horn of the spinal cord where it is located in dense core vesicles in C-fiber terminals. Peripheral inflammation substantially up-regulates BDNF mRNA and protein in the dorsal root ganglion (DRG) in a nerve growth factor-dependent fashion and results in novel expression of BDNF by DRG neurons with myelinated axons. C-fiber electrical activity also increases BDNF expression in the DRG, and both inflammation and activity increase full-length TrkB receptor levels in the dorsal horn. Sequestration of endogenous BDNF/neurotrophin 4 by intraspinal TrkB-Fc fusion protein administration does not, in noninflamed animals, change basal pain sensitivity nor the mechanical hypersensitivity induced by peripheral capsaicin administration, a measure of C fiber-mediated central sensitization. TrkB-Fc administration also does not modify basal inflammatory pain hypersensitivity, but does block the progressive hypersensitivity elicited by low-intensity tactile stimulation of inflamed tissue. BDNF, by virtue of its nerve growth factor regulation in sensory neurons including novel expression in A fibers, has a role as a central modulator of tactile stimulus-induced inflammatory pain hypersensitivity.

Animals↗
PubMed1999

Axonal regeneration from injured dorsal roots into the spinal cord of adult rats.

Injury to the central processes of primary sensory neurons produces less profound changes in the expression of growth-related molecules and less vigorous axonal regeneration than does injury to their peripheral processes. The left L4, L5, and L6 dorsal roots of deeply anaesthetized adult Sprague-Dawley rats were severed and reanastomosed, and in some animals, the ipsilateral sciatic nerve was crushed to increase the expression of growth-related molecules. After between 28 days and three months, the sciatic nerve of most animals was injected with transganglionic tracers and the animals were killed 2-3 days later. Other animals were perfused for electron microscopy. Very few regenerating axons entered the spinal cord of the rats without sciatic nerve injuries. Labelled axons, however, were always found in the spinal cord of rats with sciatic nerve injuries. They often entered the cord around blood vessels, ran rostrally within the superficial dorsal horn, and avoided the degenerating white matter. The animals with a conditioning sciatic nerve crush had many more myelinated axons around the dorsal root entry zone (DREZ) and on the surface of the cord. Thus, a conditioning lesion of their peripheral processes increased the ability of the central processes of myelinated A fibres to regenerate, including to sites (such as lamina II) they do not normally occupy. Astrocytes, oligodendrocytes, and meningeal fibroblasts in and around the DREZ may have inhibited regeneration in that region, but growth of the axons into the deep grey matter and degenerated dorsal column was also blocked.

Animals↗
PubMed1999

Transcriptional and posttranslational plasticity and the generation of inflammatory pain.

Inflammatory pain manifests as spontaneous pain and pain hypersensitivity. Spontaneous pain reflects direct activation of specific receptors on nociceptor terminals by inflammatory mediators. Pain hypersensitivity is the consequence of early posttranslational changes, both in the peripheral terminals of the nociceptor and in dorsal horn neurons, as well as later transcription-dependent changes in effector genes, again in primary sensory and dorsal horn neurons. This inflammatory neuroplasticity is the consequence of a combination of activity-dependent changes in the neurons and specific signal molecules initiating particular signal-transduction pathways. These pathways phosphorylate membrane proteins, changing their function, and activate transcription factors, altering gene expression. Two distinct aspects of sensory neuron function are changed as a result of these processes, basal sensitivity, or the capacity of peripheral stimuli to evoke pain, and stimulus-evoked hypersensitivity, the capacity of certain inputs to generate prolonged alterations in the sensitivity of the system. Posttranslational changes largely alter basal sensitivity. Transcriptional changes both potentiate the system and alter neuronal phenotype. Potentiation occurs as a result of the up-regulation in the dorsal root ganglion of centrally acting neuromodulators and simultaneously in the dorsal horn of their receptors. This means that the response to subsequent inputs is augmented, particularly those that induce stimulus-induced hypersensitivity. Alterations in phenotype includes the acquisition by A fibers of neurochemical features typical of C fibers, enabling these fibers to induce stimulus-evoked hypersensitivity, something only C fiber inputs normally can do. Elucidation of the molecular mechanisms responsible provides new opportunities for therapeutic approaches to managing inflammatory pain.

Animals↗