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Biomedical subjects

C J Woolf

Publications and source records attributed to C J Woolf.

At least 73 records · Page 4Linked to original sources
PubMed1997

Central changes in primary afferent fibers following peripheral nerve lesions.

Cutting or crushing rat sciatic nerve does not significantly reduce the number of central myelinated sensory axons in the dorsal roots entering the fourth and fifth lumbar segments even over very extended periods of time. Unmyelinated axons were reduced by approximately 50%, but only long after sciatic nerve lesions (four to eight months), and reinnervation of the peripheral target did not rescue these axons. This indicates that a peripheral nerve lesion sets up a slowly developing but major shift towards large afferent fiber domination of primary afferent input into the spinal cord. In addition, since myelinated axons are never lost, this is good evidence that the cells that give rise to these fibers are also not lost. If this is the case, this would indicate that adult primary sensory neurons with myelinated axons do not depend on peripheral target innervation for survival.

Age Factors↗
PubMed1997

Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha.

1. Peripheral inflammation is characterized by heightened pain sensitivity. This hyperalgesia is the consequence of the release of inflammatory mediators, cytokines and growth factors. A key participant is the induction of the neurotrophin nerve growth factor (NGF) by interleukin-1 beta (IL-1 beta). 2. Tumour necrosis factor alpha (TNF alpha) has been shown both to produce hyperalgesia and to upregulate IL-1 beta. We have now examined whether the induction of TNF alpha in inflammatory lesions contributes to inflammatory sensory hypersensitivity by inducing IL-1 beta and NGF. 3. The intraplantar injection of complete Freund's adjuvant (CFA) in adult rats produced a localized inflammation of the hindpaw with a rapid (3 h) reduction in withdrawal time in the hot plate test and in the mechanical threshold for eliciting the flexion withdrawal reflex. 4. The CFA-induced inflammation resulted in significant elevation in the levels of TNF alpha, IL-1 beta and NGF in the inflamed paw. In the case of TNF alpha, an elevation was detected at 3 h, rose substantially at 6 h, peaked at 24 h and remained elevated at 5 days, with similar but smaller changes in the contralateral non-inflamed hindpaw. No increase in serum TNF alpha was detected at 24 h post CFA injection. 5. Intraplantar recombinant murine TNF alpha injections produce a short-lived (3-6 h) dose-dependent (50-500 ng) increase in thermal and mechanical sensitivity which was significantly attenuated by prior administration of anti-NGF antiserum. 6. Intraplantar TNF alpha (100-500 ng) also elevated at 6 but not 48 h the levels of IL-1 beta and NGF in the hindpaw. 7. A single injection of anti-TNF alpha antiserum, 1 h before the CFA, at a dose sufficient to reduce the effects of a 100 ng intraplantar injection of TNF alpha, significantly delayed the onset of the resultant inflammatory hyperalgesia and reduced IL-1 beta but not NGF levels measured at 24 h. 8. The elevation of TNF alpha in inflammation, by virtue of its capacity to induce IL-1 beta and NGF, may contribute to the initiation of inflammatory hyperalgesia.

Animals↗
PubMed1996

Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons.

Pain is normally evoked only by stimuli that are sufficiently intense to activate high-threshold A(delta) and C sensory fibres, which relay the signal to the spinal cord. Peripheral inflammation leads to profoundly increased pain sensitivity: noxious stimuli generate a greater response and stimuli that are normally innocuous elicit pain. Inflammation increases the sensitivity of the peripheral terminals of A(delta) and C fibres at the site of inflammation. It also increases the excitability of spinal cord neurons, which now amplify all sensory inputs including the normally innocuous tactile stimuli that are conveyed by low-threshold A(beta) fibres. This central sensitization has been attributed to the enhanced activity of C fibres, which increase the excitability of their postsynaptic targets by releasing glutamate and the neuropeptide substance P. Here we show that inflammation results in A(beta) fibres also acquiring the capacity to increase the excitability of spinal cord neurons. This is due to a phenotypic switch in a subpopulation of these fibres so that they, like C-fibres, now express substance P. A(beta) fibres thus appear to contribute to inflammatory hypersensitivity by switching their phenotype to one resembling pain fibres, thereby enhancing synaptic transmission in the spinal cord and exaggerating the central response to innocuous stimuli.

Action Potentials↗
PubMed1996

Collateral sprouting of uninjured primary afferent A-fibers into the superficial dorsal horn of the adult rat spinal cord after topical capsaicin treatment to the sciatic nerve.

That terminals of uninjured primary sensory neurons terminating in the dorsal horn of the spinal cord can collaterally sprout was first suggested by Liu and Chambers (1958), but this has since been disputed. Recently, horseradish peroxidase conjugated to the B subunit of cholera toxin (B-HRP) and intracellular HRP injections have shown that sciatic nerve section or crush produces a long-lasting rearrangement in the organization of primary afferent central terminals, with A-fibers sprouting into lamina II, a region that normally receives only C-fiber input (Woolf et al., 1992). The mechanism of this A-fiber sprouting has been thought to involve injury-induced C-fiber transganglionic degeneration combined with myelinated A-fibers being conditioned into a regenerative growth state. In this study, we ask whether C-fiber degeneration and A-fiber conditioning are both necessary for the sprouting of A-fibers into lamina II. Local application of the C-fiber-specific neurotoxin capsaicin to the sciatic nerve has previously been shown to result in C-fiber damage and degenerative atrophy in lamina II. We have used B-HRP to transganglionically label A-fiber central terminals and have shown that 2 weeks after topical capsaicin treatment to the sciatic nerve, the pattern of B-HRP staining in the dorsal horn is indistinguishable from that seen after axotomy, with lamina II displaying novel staining in the identical region containing capsaicin-treated C-fiber central terminals. These results suggest that after C-fiber injury, uninjured A-fiber central terminals can collaterally sprout into lamina II of the dorsal horn. This phenomenon may help to explain the pain associated with C-fiber neuropathy.

Administration, Topical↗
PubMed1996

Intrinsic versus extrinsic factors in determining the regeneration of the central processes of rat dorsal root ganglion neurons: the influence of a peripheral nerve graft.

The relative contribution of intrinsic growth capacity versus extrinsic growth-promoting factors in determining the capacity of transected dorsal root axons to regenerate long distances was studied. L4 dorsal root axons regenerating into 4-cm peripheral nerve grafts on transected dorsal roots were counted. Few dorsal root myelinated axons regenerated to the distal end of the grafts by 10 weeks unless the sciatic nerve was also crushed. Regeneration of unmyelinated axons was also increased by peripheral lesions. Crush or transection of the dorsal roots without grafting did not alter GAP-43 mRNA expression in L4 dorsal root ganglion (DRG) cells. Grafting a peripheral nerve onto the cut end of an L4 dorsal root doubled the number of DRG cells expressing high levels of GAP-43 mRNA after a delay of several weeks. Peripheral nerve crush at the time of nerve grafting resulted in a very rapid rise in GAP-43 mRNA expression, which then declined to a steady level, twice that of controls, by 7 weeks. Thus, the rapid increase in the number of DRG neurons expressing high levels of GAP-43 mRNA after peripheral but not central axotomy correlates with the regeneration of central axons through nerve grafts. Because GAP-43 mRNA is slowly upregulated in a subpopulation of sensory neurons in response to exposure of their central axons to a peripheral nerve environment, environments favourable for axonal growth may act by increasing the intrinsic growth response of neurons. Lack of intrinsic growth capacity may contribute to the failure of dorsal root axons to regenerate into the spinal cord.

Animals↗
PubMed1996

Peripheral cell types contributing to the hyperalgesic action of nerve growth factor in inflammation.

The contribution of nerve growth factor (NGF) to inflammatory hyperalgesia potentially could be mediated by any of the three peripheral cell types that express trkA, the high-affinity NGF receptor: inflammatory cells, sympathetic neurons, and primary sensory neurons. To investigate their relative involvement, the effects of sympathectomy and mast cell degranulation were examined on the local inflammation produced by an intraplantar injection of complete Freund's adjuvant in the adult rat. Sympathectomy, produced by neonatal guanethidine treatment, elevated basal NGF levels in the skin but did not attenuate a further increase in NGF during inflammation. Although the onset of inflammatory hyperalgesia was delayed in sympathectomized animals, peak sensitivity was not affected and was still NGF-dependent. In contrast, mast cell degranulation produced by several days of treatment with the cationic secretagogue compound 48/80, while also increasing basal NGF levels, prevented a further increase in NGF levels and attenuated hypersensitivity during inflammation. Neither manipulation modified the inflammatory upregulation of interleukin-1beta. We conclude that sympathetic neurons contribute transiently to inflammatory hyperalgesia, but that mast cells and sensory neurons are important sites for the sustained action of NGF in producing increased sensitivity during inflammation.

Animals↗
PubMed1996

Phenotypic modification of primary sensory neurons: the role of nerve growth factor in the production of persistent pain.

Inflammation results in an early and maintained elevation in nerve growth factor (NGF) levels in inflamed tissues. Neutralizing the action of the increased NGF with specific anti-NGF antibodies substantially diminishes inflammatory hypersensitivity, indicating that this neurotrophin is a key mediator in the production of inflammatory pain. The hyperalgesic actions of NGF may in part be the consequence of an increase in sensitivity of the peripheral terminals of high threshold nociceptors either as a result of a direct action of NGF on trkA expressing sensory fibres or indirectly via the release of sensitizing mediators from trkA expressing inflammatory cells and postganglionic sympathetic neurons. NGF is also, however, retrogradely transported in sensory neurons to the dorsal root ganglion where it alters transcription of a number of proteins and peptides. This chapter reviews evidence suggesting that an NGF-mediated modification of gene expression in the dorsal root ganglion during inflammation is central to the pathophysiology of persistent pain. The phenotype changes produced by NGF during inflammation include elevation of neuropeptides which may amplify sensory input signals in the spinal cord and augment neurogenic inflammation in the periphery and the upregulation of growth related molecules which may lead to a hyperinnervation of injured tissue by promoting terminal sprouting.

Animals↗
PubMed1996

Induction of the Oct-2 transcription factor in primary sensory neurons during inflammation is nerve growth factor-dependent.

The mRNA encoding the POU family transcription factor Oct-2 is induced in cultured adult sensory neurons following treatment with nerve growth factor (NGF) but not with a variety of other growth factors. We show here that the Oct-2 mRNA is also upregulated in vivo in sensory neurons innervating inflamed tissue following intraplantar injection of complete Freund's adjuvant. This rise is abolished by systemic administration of anti-NGF neutralizing antibodies indicating that it is an NGF-dependent effect. Hence a very specific aspect of the NGF response occurs in sensory neurons innervating inflamed tissue in vivo. In turn, the induction of Oct-2 may play a role in the other changes observed in such neurons both in gene expression and in their ability to respond to painful stimuli.

Animals↗
PubMed1996

Zinc reduces the hyperalgesia and upregulation of NGF and IL-1 beta produced by peripheral inflammation in the rat.

The effect of systemic zinc administration on the inflammatory hyperalgesia induced by intraplantar injections of either complete Freund's adjuvant (CFA) or bacterial endotoxin/lipopolysaccharide (LPS) in a hindpaw of adult rats was investigated. CFA injection resulted in mechanical and thermal hyperalgesia and an elevation in the levels of interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) in the ipsilateral hindpaw. Zinc treatment (20 nmole) significantly reduced sensitivity in the early phase of the inflammation and diminished the increase in the levels of IL-1 beta and NGF without affecting paw swelling. Intraplantar LPS injection also produced mechanical hyperalgesia and this too was reduced by zinc administration in a dose-dependent fashion (0.1-20 nmoles). Our results indicate that zinc has an analgesic action during early inflammation and that this may be the consequence of reducing levels of the inflammatory cytokine IL-beta and the growth factor NGF.

Animals↗
PubMed1996

Basal and touch-evoked fos-like immunoreactivity during experimental inflammation in the rat.

Fos-immunoreactivity can readily be induced in spinal cord neurones by noxious, but to a much more limited extent, by innocuous peripheral stimuli. The present study has investigated whether low intensity stimuli and electrical stimulation of A beta afferents elicit greater c-fos expression during the behavioural sensory hypersensitivity generated by experimental peripheral inflammation. We have examined the time-course of c-fos expression after inflammation produced by either an intra-plantar injection of the irritant turpentine oil or of complete Freund's adjuvant (CFA). In the former case, a significant initial expression in all dorsal horn laminae was followed by a gradual decrease, whereas after CFA injection, an initial expression limited to the superficial laminae subsequently extended into the deep laminae, with a decrease at 24 h and an increase in labelling at later times. Low intensity touch stimuli repeated for 10 min, when applied at 24 h and 48 h after CFA injection, elicited a significant increase in the number of Fos-immunoreactive neurons in both the superficial and deep laminae of the dorsal horn compared to non-inflamed animals. Electrical stimulation of the sciatic nerve 24 h post-CFA injection, at a strength sufficient only to activate A beta-afferents fibres (100 microA, 50 microseconds, 10 min), also elicited a significant increase in labelling relative to the same stimuli applied in control animals, especially in laminae V-VI. The present results demonstrate that low intensity cutaneous stimuli elicit a significantly greater increase in c-fos expression in dorsal horn neurons during peripheral inflammation and that A beta-afferent input contributes to this, a finding that may relate to the allodynia experienced during inflammation.

Afferent Pathways↗
PubMed1996

Glutamate-mediated slow synaptic currents in neonatal rat deep dorsal horn neurons in vitro.

1. The role of glutamate in slow excitatory synaptic transmission between small-diameter primary afferents and deep dorsal horn neurons was examined in neonatal rat spinal cord in vitro with the use of the whole cell voltage-clamp technique. 2. Single-shock electrical stimulation of large-diameter A beta-fibers evoked a short-latency (< 10 ms) fast (< 500 ms) excitatory postsynaptic current (EPSC). Stimulation of small-diameter A delta- and C fibers resulted, in addition, in a slowly rising and decaying EPSC (lasting up to 14 s) following the fast EPSC. The slow EPSC was never observed with stimulation of A beta-fibers. 3. Two patterns of EPSCs were observed, "type 1" and "type 2," which differed in their time course (lasting up to 1 and 14 s, respectively). The type 1 response was biphasic, with a fast monosynaptic component followed by an invariant, presumably monosynaptic, late slow component. The type 2 response was multiphasic, with a fast monosynaptic component followed by a slow component composed of fast polysynaptic currents superimposed on a slow current. 4. The fast monosynaptic component had a linear conductance, whereas the late slower component of the A beta-fiber-evoked response had a negative slope conductance at holding potentials more negative than -23 mV. Both currents reversed at a membrane potential of -1.2 +/- 2.8 (SE) mV. 5. With the use of selective non-N-methyl-D-aspartate (non-NMDA) and NMDA receptor antagonists [6-cyano-7-nitroquinox-aline-2,3-dione (CNQX) or 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo (F) quinoxaline and D(-)-2-amino-5-phosphonopentanoic acid (D-AP5), respectively] we showed that both the early fast (A beta-fiber evoked) and the late slow (A delta- and C fiber evoked) components were mediated by non-NMDA and NMDA receptors. CNQX suppressed both the early fast and late slow components of the compound EPSC, whereas D-AP5 suppressed the polysynaptic currents of the early fast component and the late slow component without significantly affecting the early fast monosynaptic component. 6. Slow EPSCs summated on low-frequency (1 or 10 Hz), repetitive stimulation and produced long-duration "tail" currents on cessation of the stimulus. The amount of temporal summation was proportional to the duration of the slow EPSC and the frequency of stimulation. 7. Our results suggest that slow ionotropic-glutamate-receptor-mediated EPSCs produced by the stimulation of small-diameter primary afferents play an important role in activity-dependent synaptic plasticity in the dorsal horn.

Animals↗
PubMed1995

Reorganization of central terminals of myelinated primary afferents in the rat dorsal horn following peripheral axotomy.

We have investigated the time course and extent to which peripheral nerve lesions cause a morphological reorganization of the central terminals of choleragenoid-horseradish peroxidase (B-HRP)-labelled primary afferent fibers in the mammalian dorsal horn. Choleragenoid-horseradish peroxidase is retrogradely transported by myelinated (A) sensory axons to laminae I, III, IV and V of the normal dorsal horn of the spinal cord, leaving lamina II unlabelled. We previously showed that peripheral axotomy results in the sprouting of numerous B-HRP-labelled large myelinated sensory axons into lamina II. We show here that this spread of B-HRP-labelled axons into lamina II is detectable at 1 week, maximal by 2 weeks and persists for over 6 months postlesion. By 9 months, however, B-HRP fibers no longer appear in lamina II. The sprouting into lamina II occurs whether regeneration is allowed (crush) or prevented (section with ligation), and does not reverse at times when peripheral fibers reinnervate the periphery. We also show that 15 times more synaptic terminals in lamina II are labelled by B-HRP 2 weeks after axotomy than in the normal. We interpret this as indicating that the sprouting fibers are making synaptic contacts with postsynaptic targets. This implies that A-fiber terminal reorganization is a prominent and long-lasting but not permanent feature of peripheral axotomy. We also provide evidence that this sprouting is the consequence of a combination of an atrophic loss of central synaptic terminals and the conditioning of the sensory neurons by peripheral axotomy. The sprouting of large sensory fibers into the spinal territory where postsynaptic targets usually receive only small afferent fiber input may bear on the intractable touch-evoked pain that can follow nerve injury.

Afferent Pathways↗
PubMed1995

Involvement of neurokinin receptors in the induction but not the maintenance of mechanical allodynia in rat flexor motoneurones.

1. Intrathecal (i.t.) injections of the (tachykinin) NK1 receptor agonist, substance P methyl ester (SPME; 20 pmol), or the NK2 receptor agonist, neurokinin A (NKA; 20 pmol), substantially decreased the cutaneous mechanical threshold and markedly enhanced the touch-evoked response of posterior biceps femoris-semitendinosus (PBF-ST) spinal flexor motoneurones in decerebrate-spinal rats. This cutaneous mechanical reflex allodynia was prevented by pretreatment with the NK1 antagonist RP 67580 (2.28 nmol, i.t.) and the NK2 antagonist MEN 10376 (0.7 nmol, i.t.), respectively. 2. Electrical stimulation of the sural nerve at C fibre strength or cutaneous application of the irritant, mustard oil, produced prolonged cutaneous mechanical allodynia in PBF-ST motoneurones (15 min and > 1 h, respectively). Pretreatment with RP 67580 but not MEN 10376 prevented this, but when RP 67580 was administered 25 min after the application of mustard oil, the established hypersensitivity of the flexor motor reflex was not reversed. The enantiomer of RP 67580, RP 68651 was without effect. 3. Injection of bradykinin (60 microM, 80 microliters) into the gastrocnemius muscle increased the cutaneous mechanical hypersensitivity of PBF-ST flexor motoneurones for 40-50 min. MEN 10376, but not RP 67580, prevented this, but only when administered prior to the bradykinin injection. 4. These results suggest that the induction, but not the maintenance, of cutaneous mechanical allodynia in flexor motoneurones is NK receptor dependent, with cutaneous C fibre conditioning inputs acting via NK1 and muscle C fibre conditioning inputs via NK2 receptor subtypes.

Animals↗
PubMed1995

Morphine selectively depresses the slowest, NMDA-independent component of C-fibre-evoked synaptic activity in the rat spinal cord in vitro.

The effects of morphine on the depolarizing synaptic responses produced in motoneurons by electrical stimulation of primary sensory neurones have been recorded in hemisected spinal cord preparations (8- to 12-day-old rat pups). Morphine at concentrations of 0.1-20 microM reduced a slow, long-lasting (latency greater than 1 s, duration up to 10 s) component of the ventral root potential (VRP) evoked by C-fibre strength stimulation of the dorsal root. At 2 microM the reduction in area of this slow synaptic potential was 71.7 +/- 0.9% of control values (n = 15). The earliest components of the C-fibre strength VRP (the first 100 ms) and the responses to A beta strength stimuli were unaffected by the opioid even at 10-20 microM. The intermediate, NMDA receptor antagonist (D-AP5, 40 microM)-sensitive component (which lasts 100-1000 ms) was reduced by 34 +/- 2.2% of control (n = 15), which was significantly less than the reduction of the later NMDA-independent component (P < 0.001). Morphine (0.1-20 microM) also depressed the cumulative depolarization generated by the temporal summation of synaptic responses evoked by brief trains of C-fibre strength stimuli (1 or 10 Hz). A significantly greater reduction at the lower frequency of stimulation (56.3 +/- 2.0%) than at the higher (20.3 +/- 1.69%, n = 10, measured at 2 microM morphine) was found (P < 0.005). The effects of morphine were reversible upon wash-out or superfusion with the opioid receptor antagonist naloxone (2 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1995

Nerve growth factor contributes to the up-regulation of growth-associated protein 43 and preprotachykinin A messenger RNAs in primary sensory neurons following peripheral inflammation.

Peripheral inflammation induced in adult rats by an intraplantar injection of complete Freund's adjuvant results in a rapid (6 h) increase in the expression of the messenger RNAs for the neuronal growth-associated protein 43 and for preprotachykinin A, the precursor for substance P, in dorsal root ganglion sensory neurons innervating the inflamed area. This increase peaks at 48 h and then declines by five days. The changes are present in the dorsal root ganglion cells innervating the inflamed skin (lumbar 4 or 5) but no elevation was found in the third lumbar dorsal root ganglion which innervates neighbouring non-inflamed skin. The increased growth-associated protein 43 messenger RNA in the dorsal root ganglion is followed by a marked increase in growth-associated protein 43-like immunoreactive fibres in the epidermis of the inflamed skin. Systemic administration of neutralizing anti-nerve growth factor antibodies immediately prior to the inflammation prevents the increase in growth-associated protein 43 and preprotachykinin A messenger RNAs in the sensory neurons. A subcutaneous injection of nerve growth factor (200 ng) into the hindpaw elevates preprotachykinin A but not growth-associated protein 43 messenger RNA in the fourth lumbar dorsal root ganglion 48 h post-injection and this could be prevented by co-administration of the anti-nerve growth factor serum. The production of nerve growth factor in inflamed target tissues leads to alterations in the phenotype of responsive adult primary sensory neurons which include a change in the levels of a growth-related protein and a peptide neuromodulator.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Is there any clinical advantage of increasing the pre-emptive dose of morphine or combining pre-incisional with postoperative morphine administration?

Pre-emptive treatment with an i.v. infusion of morphine 10 mg at induction reduces postoperative analgesic requirement and wound hypersensitivity compared with the same dose administered at the end of operation. Increasing the dose of preemptive morphine may potentially reduce postoperative pain further, while administering morphine at the end of operation, in addition to the beginning, may reduce pain generated by the sensory activity elicited from the wound in the immediate postoperative period. To examine this we have conducted a randomized, double-blind study in patients undergoing abdominal hysterectomy to compare the effect of morphine 20 mg administered before operation with 10 mg at induction and 10 mg on closure of the peritoneum. Postoperative pain was assessed by visual analogue score (VAS) at rest and on movement and by total morphine consumption administered by patient-controlled analgesia (PCA). Wound sensitivity was assessed by von Frey pain thresholds. Both groups had similar morphine consumption, VAS scores and touch and pain thresholds, and in both, secondary hyperalgesia was prevented. Nausea and vomiting scores were higher in the 20-mg group. There was no significant difference between the two groups and neither regimen appeared to offer obvious clinical advantages compared with a lower dose (10 mg) morphine analgesic strategy. Therefore, there may be a ceiling effect to the production of pre-emptive analgesia by morphine.

Adult↗