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Clifford J Woolf

Publications and source records attributed to Clifford J Woolf.

At least 73 records · Page 4Linked to original sources
PubMed2002

ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity.

Activation of ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinase in dorsal horn neurons of the spinal cord by peripheral noxious stimulation contributes to short-term pain hypersensitivity. We investigated ERK activation by peripheral inflammation and its involvement in regulating gene expression in the spinal cord and in contributing to inflammatory pain hypersensitivity. Injection of complete Freund's adjuvant (CFA) into a hindpaw produced a persistent inflammation and a sustained ERK activation in neurons in the superficial layers (laminae I-IIo) of the dorsal horn. CFA also induced an upregulation of prodynorphin and neurokinin-1 (NK-1) in dorsal horn neurons, which was suppressed by intrathecal delivery of the MEK (MAP kinase kinase) inhibitor U0126. CFA-induced phospho-ERK primarily colocalized with prodynorphin and NK-1 in superficial dorsal horn neurons. Although intrathecal injection of U0126 did not affect basal pain sensitivity, it did attenuate both the establishment and maintenance of persistent inflammatory heat and mechanical hypersensitivity. Activation of the ERK pathway in a subset of nociceptive spinal neurons contributes, therefore, to persistent pain hypersensitivity, possibly via transcriptional regulation of genes, such as prodynorphin and NK-1.

Animals↗
PubMed2002

The pattern of expression of the voltage-gated sodium channels Na(v)1.8 and Na(v)1.9 does not change in uninjured primary sensory neurons in experimental neuropathic pain models.

A spared nerve injury of the sciatic nerve (SNI) or a segmental lesion of the L5 and L6 spinal nerves (SNL) lead to behavioral signs of neuropathic pain in the territory innervated by adjacent uninjured nerve fibers, while a chronic constriction injury (CCI) results in pain sensitivity in the affected area. While alterations in voltage-gated sodium channels (VGSCs) have been shown to contribute to the generation of ectopic activity in the injured neurons, little is known about changes in VGSCs in the neighboring intact dorsal root ganglion (DRG) neurons, even though these cells begin to fire spontaneously. We have now investigated changes in the expression of the TTX-resistant VGSCs, Nav1.8 (SNS/PN3) and Nav1.9 (SNS2/NaN) by immunohistochemistry in rat models of neuropathic pain both with an intermingling of intact and degenerated axons in the nerve stump (SNL and CCI) and with a co-mingling in the same DRG of neurons with injured and uninjured axons (sciatic axotomy and SNI). The expression of Nav1.8 and Nav1.9 protein was abolished in all injured DRG neurons, in all models. In intact DRGs and in neighboring non-injured neurons, the expression and the distribution among the A- and C-fiber neuronal populations of Nav1.8 and Nav1.9 was, however, unchanged. While it is unlikely, therefore, that a change in the expression of TTX-resistant VGSCs in non-injured neurons contributes to neuropathic pain, it is essential that molecular alterations in both injured and non-injured neurons in neuropathic pain models are investigated.

Animals↗
PubMed2002

Progressive tactile hypersensitivity after a peripheral nerve crush: non-noxious mechanical stimulus-induced neuropathic pain.

Neuropathic pain syndromes are characterized by spontaneous pain and by stimulus-evoked allodynia and hyperalgesia. Stimulus-induced pain, i.e. the capacity of external stimuli to alter sensory processing so as to generate a pain hypersensitivity that outlasts the initiating stimulus, is usually present only after intense activation of nociceptors. In abnormal pain states, however, such as after capsaicin injection or inflammation, a stimulus-induced incremental pain can be generated by repetitive light touch, termed progressive tactile hypersensitivity (PTH). In the present study, we have examined whether PTH also occurs in two experimental models of neuropathic pain: a crush injury of the sciatic nerve and the spared nerve injury (SNI) model. When applied during the first weeks after injury to the territory of the injured crushed nerve, repeated low-intensity mechanical stimulation did not change the mechanical withdrawal threshold response. However, 10 weeks and after, the same repeated stimulation induced a progressive tactile hypersensitivity that persisted after discontinuation of the tactile stimulation. Following SNI, repeated stimulation of the hypersensitive skin territory, corresponding to the intact spared sural nerve, never induced PTH. Tactile stimulation of regenerating afferents but not spared non-injured afferents, can induce, therefore, PTH and such a stimulus-induced alteration in pain processing may contribute to clinical neuropathic pain.

Animals↗
PubMed2002

Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets.

Advances in our understanding of the synthesis, regulation and function of prostanoids have led to a new appreciation of their actions in health and disease. Prostanoid synthesis is essential for the generation of inflammatory pain and this depends not only on prostanoid production at the site of inflammation, but also on the actions of prostanoids synthesized within the central nervous system (CNS). Moreover, central prostanoid synthesis is controlled both by neural and humoral signals, the latter being a novel form of input to the CNS. Diverse compounds that act along the pathway of prostanoid synthesis and action, both in the periphery and in the CNS, might provide increased benefit for treating inflammatory pain hypersensitivity and its associated sickness syndrome, with a reduced risk of adverse effects.

Arachidonic Acid↗
PubMed2002

Can we conquer pain?

Pain can be an adaptive sensation, an early warning to protect the body from tissue injury. By the introduction of hypersensitivity to normally innocuous stimuli, pain may also aid in repair after tissue damage. Pain can also be maladaptive, reflecting pathological function of the nervous system. Multiple molecular and cellular mechanisms operate alone and in combination within the peripheral and central nervous systems to produce the different forms of pain. Elucidation of these mechanisms is key to the development of treatments that specifically target underlying causes rather than just symptoms. This new approach promises to revolutionize pain diagnosis and management.

Afferent Pathways↗
PubMed2002

A single preoperative oral dose of valdecoxib, a new cyclooxygenase-2 specific inhibitor, relieves post-oral surgery or bunionectomy pain.

BACKGROUND: The trend toward day-case surgery, with discharge on oral medication, has highlighted the need for effective and safe analgesics that facilitate a rapid recovery and discharge time. This study evaluated the analgesic efficacy, dose dependency, duration of action, and safety of the cyclooxygenase-2 specific inhibitor, valdecoxib, administered before oral or orthopedic surgery. METHODS: Eligible healthy adult patients were scheduled to undergo either extraction of two impacted third molar teeth (n = 284) or bunionectomy surgery (n = 223) with local anesthesia in two randomized, double-blind, placebo-controlled studies conducted at three centers in the United States. Patients received a single, preoperatively administered oral dose of placebo or 10 (oral surgery only), 20, 40, or 80 mg valdecoxib. Analgesic efficacy was assessed postoperatively, over a 24-h treatment period, or until the patient required rescue medication. Efficacy measures included time to rescue medication, proportion of patients requiring such rescue, pain intensity, and the Patient's Global Evaluation of Study Medication. RESULTS: In both studies, all doses of valdecoxib produced analgesia with a duration (time to rescue analgesia) and magnitude (Pain Intensity, Patient's Global Evaluation) significantly greater than placebo. A dose-dependent effect was observed up to 40 mg valdecoxib, with an 80-mg dose providing no additional analgesic benefit. In both models, all doses of valdecoxib were well tolerated, with no clinically significant treatment-related gastrointestinal, renal, or platelet-derived adverse events, and no evidence of a dose-related increase in adverse events. CONCLUSIONS: Preoperative orally administered valdecoxib provides well-tolerated and effective analgesia for mild to moderate postoperative pain.

Adult↗
PubMed2000

Spared nerve injury: an animal model of persistent peripheral neuropathic pain.

Peripheral neuropathic pain is produced by multiple etiological factors that initiate a number of diverse mechanisms operating at different sites and at different times and expressed both within, and across different disease states. Unraveling the mechanisms involved requires laboratory animal models that replicate as far as possible, the different pathophysiological changes present in patients. It is unlikely that a single animal model will include the full range of neuropathic pain mechanisms. A feature of several animal models of peripheral neuropathic pain is partial denervation. In the most frequently used models a mixture of intact and injured fibers is created by loose ligation of either the whole (Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107) or a tight ligation of a part (Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990;43:205-218) of a large peripheral nerve, or a tight ligation of an entire spinal segmental nerve (Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50:355-363). We have developed a variant of partial denervation, the spared nerve injury model. This involves a lesion of two of the three terminal branches of the sciatic nerve (tibial and common peroneal nerves) leaving the remaining sural nerve intact. The spared nerve injury model differs from the Chung spinal segmental nerve, the Bennett chronic constriction injury and the Seltzer partial sciatic nerve injury models in that the co-mingling of distal intact axons with degenerating axons is restricted, and it permits behavioral testing of the non-injured skin territories adjacent to the denervated areas. The spared nerve injury model results in early (<24 h), prolonged (>6 months), robust (all animals are responders) behavioral modifications. The mechanical (von Frey and pinprick) sensitivity and thermal (hot and cold) responsiveness is increased in the ipsilateral sural and to a lesser extent saphenous territories, without any change in heat thermal thresholds. Crush injury of the tibial and common peroneal nerves produce similar early changes, which return, however to baseline at 7-9 weeks. The spared nerve injury model may provide, therefore, an additional resource for unraveling the mechanisms responsible for the production of neuropathic pain.

Animals↗
PubMed1999

Implications of recent advances in the understanding of pain pathophysiology for the assessment of pain in patients.

As we approach the new millennium, it is clear that we are on the brink of a major change in clinical pain management. We are poised to move from a treatment paradigm that has been almost entirely empirical to one that will be derived from an understanding of the actual mechanisms involved in the pathogenesis of pain. When this is achieved, pain treatment will at last be rationally based. The implications of this are immense and will necessitate major changes in the way we classify pain, which until now has been based on disease, duration and anatomy, to a mechanism-based classification. In addition, the assessment, diagnosis and treatment of pain will change. The aim in the future will be to identify in individual patients what mechanisms are responsible for their pain and to target treatment specifically at those mechanisms. We present for discussion, a new approach for classifying pain, based on an analysis of mechanisms, and show how this could be used to assess pain clinically. Such kinds of pain assessment, which need to be designed to reveal as much as possible about mechanisms, are necessary for more sophisticated epidemiology and clinical research as well as for providing the outcome measures necessary for the evaluation of the efficacy of new treatments targeted at particular pain mechanisms.

Humans↗
PubMed1998

Morphine, the NMDA receptor antagonist MK801 and the tachykinin NK1 receptor antagonist RP67580 attenuate the development of inflammation-induced progressive tactile hypersensitivity.

Normally-innocuous low-intensity tactile stimuli applied to inflamed tissue induce a progressive decrease in the mechanical flexion withdrawal threshold, the phenomenon of progressive tactile hypersensitivity (PTH). The effects of the mu opioid receptor agonist morphine, the non-competitive NMDA receptor antagonist MK801 and the tachykinin NK1 receptor antagonist RP67580 on the development and maintenance of PTH has now been investigated behaviourally in rats inflamed 48 h earlier by intraplantar complete Freund's adjuvant injection. A standard protocol of eight light tactile stimuli applied to the dorsum of the inflamed paw every 4 s at 5 min intervals resulted, over 60 min, in a 70% fall in mechanical threshold from the pre-conditioning baseline value. Morphine administered before the tactile stimuli at 0.05 mg/kg i.p. had no effect on either baseline thresholds or PTH. At 0.5 mg/kg, morphine prevented the establishment of PTH without changing baseline thresholds. At 5 mg/kg morphine produced analgesia, increasing thresholds above the baseline. MK801 pre-treatment at 0.01 and 0.001 mg/kg i.p. significantly attenuated the development of progressive tactile hyperalgesia without an effect on basal thresholds. RP67580 pre-treatment at 0.1 mg/kg i.p. had no effect, but at both I and 10 mg/kg, attenuated progressive tactile hypersensitivity without changing baseline values. To test the effect of the drugs on established PTH, they were administered 90 min after the commencement of intermittent tactile stimulation to the inflamed hindpaw, when thresholds had reached a plateau. Morphine (0.5 mg/kg) and MK801 (0.01 mg/kg) produced only a small reduction in sensitivity and RP67580 (1 mg/kg) had no effect. These results suggest that the induction of inflammatory progressive tactile hypersensitivity is sensitive to morphine, and to a lesser extent NMDA and NKI receptor antagonists, but these compounds at a dose that do not alter baseline values, do not normalise established tactile hypersensitivity.

Analgesics↗
PubMed1996

Lignocaine selectively reduces C fibre-evoked neuronal activity in rat spinal cord in vitro by decreasing N-methyl-D-aspartate and neurokinin receptor-mediated post-synaptic depolarizations; implications for the development of novel centrally acting analgesics.

The action of lignocaine on nociceptive transmission in the spinal cord has been studied in vitro using ventral root potential (VRP) recordings from 10-12-day-old rat hemisected spinal cord preparations. Single-shock stimulation of a dorsal root at intensities sufficient to activate high-threshold C-primary afferent fibres elicited VRPs lasting for 15-20 sec in the corresponding ventral root. The VRP consisted of 3 distinct parts: the early, slow and prolonged components, as previously described (Thompson et al. 1992), where the early represents A beta fibre-evoked mono- and polysynaptic responses lasting for tens of milliseconds, the slow is a largely N-methyl-D-aspartic acid (NMDA) receptor-mediated small-calibre afferent-generated component, lasting for about 1.5 sec, and the prolonged is a neurokinin receptor-mediated long-lasting component generated by high-threshold fibres. Lignocaine superfusion (40-60 microM) significantly and reversibly reduced the slow and prolonged components of the C fibre-evoked VRP in a dose-dependent manner without any effect on the early or A beta fibre-mediated component of the VRP. The amplitude of the cumulative VRP generated by repetitive inputs (1 and 10 Hz) was also significantly reduced as was the depolarization produced by bath application of NMDA (100 microM) or substance P (SP, 1 microM) in the presence or absence of tetrodotoxin (TTX) (300 nM). At this dose range lignocaine had no effect on the compound action potential (CAP) elicited by stimulating the sciatic nerve and recorded on the dorsal root. The CAP was only significantly reduced with a 300 microM dose of lignocaine. Application of the opiate, glycine, GABAA and GABAB receptor antagonists, naloxone (1 microM), strychnine (100 microM), bicuculline (100 microM) and phaclofen (100 microM) did not alter the depressant effects of lignocaine on the VRP. Low concentrations of lignocaine have a selective action on nociceptive transmission in the spinal cord which is different and more potent than its local anaesthetic conduction blockade in the periphery. This includes a reduction of direct or synaptically driven NMDA- and NK receptor-mediated post-synaptic depolarizations indicating that this class of sodium channel blockers may be potentially useful as analgesic agents, possibly acting on TTX-resistant sodium ion channels.

Analgesics↗
PubMed1996

Progressive tactile hypersensitivity: an inflammation-induced incremental increase in the excitability of the spinal cord.

Two established phenomena contribute to the generation of post-injury pain hypersensitivity: peripheral sensitization, an increase in transduction sensitivity of high threshold A delta and C-fibre nociceptors, and central sensitization, an increase in excitability of neurones in the spinal cord triggered exclusively by C-fibre inputs. We now describe a novel phenomenon: progressive tactile hypersensitivity, which contributes to a cumulative allodynia during inflammation. Behavioural measurements in conscious intact animals showed that repeated light touch stimuli delivered at 5-min intervals to an inflamed paw, established 48 h earlier by an intra-plantar injection of complete Freund's adjuvant (CFA), resulted in a progressive reduction in the mechanical withdrawal threshold by more than 75%, from its already hypersensitive basal level. This hypersensitive state persisted for several hours after discontinuing the touch stimuli and did not occur in non-inflamed animals. To monitor nociceptive processing and the afferent fibres responsible, we also measured activity in posterior biceps femoris/semitendinosus flexor motor neurones. In non-inflamed decerebrate-spinal rats, the cutaneous mechanical threshold and pinch-evoked activity of these neurones are stable when tested repeatedly at 5-min intervals and are characterised by absent or small responses to low intensity mechanical stimuli or electrical activation of A beta-fibres. In inflamed animals, the spontaneous activity, touch-, pinch- and A beta-afferent-evoked responses of hamstring flexor motor neurones are significantly increased. The flexor reflex becomes, moreover, progressively more sensitized by repetition every 5 min, of standard mechanical stimuli (touch and pinch), that do not modify excitability in control non-inflamed animals. A cumulative increase in A beta-afferent-evoked responses also occurs when the test stimulus only comprises stimulation of the sural nerve at A beta strength (10 Hz, 10 sec), showing that A beta-afferents have the capacity to produce progressive hypersensitivity. Progressive hypersensitivity, measured here as a progressive tactile allodynia after inflammation in either intact or decerebrate-spinal rats, with its gradual build-up and contribution from A beta fibres, is very different from the central sensitization induced by C-fibre stimulation which is characterised by a peak increase in excitability soon after the conditioning input followed by a steady decrement to baseline levels. Progressive hypersensitivity is likely to be the consequence of an alteration in the function and phenotype of afferents innervating inflamed tissue and the pattern of excitation they produce in spinal neurones. The phenomenon may have an important role in the development of inflammatory pain and hypersensitivity.

Animals↗
PubMed1995

Noxious stimuli induce an N-methyl-D-aspartate receptor-dependent hypersensitivity of the flexion withdrawal reflex to touch: implications for the treatment of mechanical allodynia.

Primary C-fiber afferents can induce a state of increased excitability in spinal cord neurons amplifying their responsiveness to noxious and innocuous stimuli--the phenomenon of central sensitization. We have examined whether the hypersensitivity to low-intensity stimuli (mechanical allodynia) evoked by C-afferent conditioning inputs is NMDA receptor dependent. The enhancement by C-afferent conditioning stimuli of the normally low or absent cutaneous touch-evoked responses of posterior biceps femoris/semitendinosus flexor motoneurons in the decerebrate-spinal rat has been used as a model of touch-evoked allodynia. Three different noxious conditioning stimuli (electrical stimulation of the sural nerve at C-fiber strength, cutaneous application of mustard oil and the intramuscular (i.m.) injection of bradykinin) enhanced touch-evoked responses and decreased the threshold of the flexor reflex to mechanical stimulation. Intrathecal (i.t.) injections of NMDA (20 pmol) produced a similar effect. A non-competitive NMDA antagonist MK 801, administered prior to the conditioning input at doses that did not modify the baseline reflex, significantly attenuated both the enhancement of touch-evoked responses and the threshold decrease following the noxious conditioning stimuli. Treatment with MK 801 some time after the conditioning input when the mechanical hypersensitivity is fully established, also reduced the increased touch-evoked responses. The reduction in threshold and the increase in touch responsiveness induced by cutaneous and muscle noxious C-fiber conditioning stimuli in the rat spinal cord are, therefore, both prevented and reversed by NMDA receptor antagonism. NMDA antagonists may be potentially useful, therefore, in treating postinjury pain hypersensitivity.

Animals↗
PubMed1994

Sensitization of high mechanothreshold superficial dorsal horn and flexor motor neurones following chemosensitive primary afferent activation.

Nociceptive primary afferents have the capacity to induce a state of increased excitability or central sensitization in dorsal horn neurones. This contributes to the mechanical hypersensitivity (allodynia) which occurs after peripheral tissue injury where low-mechanothreshold primary afferent activation begins to elicit pain. The relative susceptibility of dorsal horn cells with an apparent exclusive nociceptive input (nociceptive-specific (NS) or high-threshold (HT) cells) and those with a convergent input from low- and high-threshold mechanoreceptors (wide-dynamic-range (WDR) or multireceptive neurones) to sensitivity changes has been disputed. We have examined whether high-mechanothreshold neurones in the superficial dorsal and the ventral horn can modify their sensitivity following cutaneous application of the chemical irritant mustard oil. This produced both a prolonged reduction in the mechanical threshold of the cutaneous flexion withdrawal reflex, recorded from semitendinosus alpha-motor neurones, and an increase in the activity evoked in these neurones by low-intensity touch stimuli to the glabrous skin. Eight NS or HT only cells, defined in terms of their cutaneous mechanoreceptive field properties, were recorded in the superficial dorsal horn before and after cutaneous application of mustard oil. Mustard oil was applied outside of the mechanical receptive field of the cells and produced a transient increase in action potential discharge in 4 cells but increased the mechanoreceptive field size in all cells for 30-60 min. Mechanical thresholds declined in 6 cells to levels associated with low-threshold (LT) and WDR cells, and this was accompanied by recruitment of a novel brush/touch response in 5 cells. The responses evoked by graded electrical stimulation of the sural nerve were tested in 5 cells. Only 1 cell failed to show any change after mustard oil. In 3 cells, an increase in the response to A-fibre afferents occurred, a novel A-fibre response was recruited in 2 cells and the C-fibre response increased in 2 cells. Cells in the superficial dorsal horn of the rat spinal cord that are normally NS can begin, therefore, to respond to LT primary afferent mechanoreceptors after an increase in central excitability produced by activation of peripheral chemoreceptors. Sensitization of these, as well as of WDR cells, may contribute to the generation of post-injury mechanical pain and reflex hypersensitivity.

Animals↗
PubMed1991

The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states.

Repetitive stimulation of small diameter primary afferent fibres produces a progressive increase in action potential discharge (windup) and a prolonged increase in the excitability of neurones in the spinal cord following the stimulus. Previous studies have demonstrated that windup is the consequence of the temporal summation of slow synaptic potentials and that the slow potentials and windup are reduced by pretreatment with N-methyl-D-aspartic acid (NMDA) antagonists. We have now examined whether primary afferent induced hypersensitivity states in flexor motoneurones are also dependent on the activation of NMDA receptors and whether windup is a possible trigger for the production of the central hypersensitivity. Both a non-competitive (MK-801) and a competitive (D-CPP) NMDA antagonist, at doses that did not modify the baseline reflex, reduced the facilitation of the flexor reflex produced by either brief electrical stimulation of the sural nerve (1 Hz for 20 sec at C-fibre strength), or by the cutaneous application of the chemical irritant mustard oil. These antagonists also prevented windup from occurring in the motoneurones. When the the MK-801 and the D-CPP were administered once a state of central facilitation had been induced by prior treatment with mustard oil, they returned the facilitated reflex to its pretreatment level. These results indicate that NMDA receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs. Because central sensitization is likely to contribute to the post-injury pain hypersensitivity states in man, these data have a bearing both on the potential role of NMDA antagonists for pre-emptive analgesia and for treating established pain states.

Action Potentials↗
PubMed1985

The systemic administration of local anaesthetics produces a selective depression of C-afferent fibre evoked activity in the spinal cord.

An electrophysiological analysis of the antinociceptive effects of systemic lidocaine and its longer acting primary amine congener, tocainide, has been performed in the decerebrate-spinal unanaesthetised rat. Neither of these local anaesthetic drugs when administered systemically in doses of up to 10 mg/kg (lidocaine) or 100 mg/kg (tocainide), produced any evidence of a block in the conduction of action potentials in A beta, A delta or C primary afferents. The local anaesthetics also failed to reduce mustard oil induced neurogenic extravasation, a test of cutaneous C-fibre terminal function. Lidocaine produced a transient (1-2 min) depression in monosynaptic reflexes at doses of greater than or equal to 1 mg/kg while tocainide had no effect on this reflex at any dose up to a 100 mg/kg. Both drugs, however, significantly suppressed the C-fibre evoked polysynaptic reflex generated by stimulating the sural nerve. The tocainide effect was longer lasting with less action on the short latency A beta-evoked reflex than lidocaine. The reflex activity in hamstring flexor alpha-motoneurones evoked by pinching the toes of the ipsilateral hind paw was reduced by both drugs but not abolished. Thermal and noxious chemical evoked reflexes were, however, completely suppressed by the local anaesthetic drugs, again with a longer action from tocainide. These results demonstrate that the systemic administration of drugs which increase the inactivation of sodium channels can produce a selective central block of certain types of afferent evoked activity in the spinal cord. There are resemblances between the selective C-fibre suppressing actions of systemically administered local anaesthetic and the pharmacological actions of narcotic opiates which may represent a similar mechanism for the analgesic action of these quite different classes of drugs.

Animals↗
PubMed1984

Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat.

Chronic decerebrate rats have been prepared by the aspiration of all the cranial contents rostral to the mesencephalon. With careful nursing, body temperature control and orogastric tube feeding the rats survive for up to 4 months. The decerebrate rats have intact brain stem and spinal reflexes including locomotion, righting reflexes and grooming. Mild noxious cutaneous thermal and mechanical stimuli of an intensity which does not produce tissue damage evokes flexion withdrawal reflexes, vocalization, orientation to the site of the injury and generalized escape or attack responses, from the animals. These effects are transient and only occur during the application of the stimulus. The rats do not exhibit stress reactions, aggression or vocalization when handled before or after application of such noxious stimuli. The production of localized tissue injury by thermal or chemical means results in long term alterations (up to 6 weeks) in the thresholds and excitability of the flexor reflex, both ipsilateral and contralateral, to the site of the injury. It is proposed that the reduction in the flexor reflex threshold is analogous to the hyperalgesia and allodynia that follows tissue injury in man and that the long term alterations in the flexor reflex in the chronic decerebrate rat provide a model for the study of chronic pain, without the ethical problems associated with such studies in intact animals.

Afferent Pathways↗
PubMed1980

The stereospecific effect of naloxone on rat dorsal horn neurones; inhibition in superficial laminae and excitation in deeper laminae.

The effect of systemic naloxone on the activity evoked by C-fibre stimulation in dorsal horn neurones of the rat spinal cord has been investigated. Recordings were made in unanaesthetized, decerebrate spinalized rats. Fifteen units were recorded from laminae 4 and 5 of the dorsal horn, 11 of these units were excited by naloxone (0.2--1.0 mg/kg). The onset of this excitation was after 20 sec to 5 min and recovery to control levels occurred within 15--40 min. Of 17 units recorded in substantia gelatinosa of the dorsal horn, 13 were inhibited by the naloxone. The latency of onset of this inhibition was short (2--10 sec) and the effect persisted for 5--10 min. The effects were largely restricted to C-fibre evoked activity although sometimes A delta responses were similarly altered. Neurones stimulated by A beta-fibre threshold, or whose sole afferent input were A beta-fibres, were unaffected by the naloxone. The stereoisomer of naloxone, (+)naloxone which is inactive in opiate receptor binding tests, failed to produce the same changes found with (-)naloxone in 17 units. These results show a differential effect of naloxone on neurones in the dorsal horn which respond to C-fibre input. Units in the substantia gelatinosa are inhibited while units in deeper laminae are excited by naloxone. These effects are likely to be mediated by the blockade of endogenous opioids in the spinal cord.

Animals↗