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Anthony H Dickenson

Publications and source records attributed to Anthony H Dickenson.

51 records · Page 3Linked to original sources
PubMed2002

A combination of gabapentin and morphine mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model of neuropathy.

BACKGROUND: Peripheral nerve damage can result in severe, long-lasting pain accompanied by sensory deficits. This neuropathic pain remains a clinical problem, and effective morphine analgesia is often limited by intolerable side effects. The antiepileptic gabapentin has recently emerged as an alternative chronic pain treatment. Improved management of the diverse symptoms and mechanisms of neuropathic pain may arise from combination therapy, based on multiple pharmacologic targets and low drug doses. METHODS: The authors used the Kim and Chung rodent model of neuropathy to induce mechanical and cold allodynia in the ipsilateral hind paw. In vivo electrophysiologic techniques were subsequently used to record evoked dorsal horn neuronal responses in which the effects of systemic morphine and gabapentin were investigated, both individually and in combination. RESULTS: Morphine (1 and 4 mg/kg) inhibited neuronal responses of control rats but not after neuropathy. Gabapentin (10 and 20 mg/kg) inhibited neuronal responses in nerve injured rats and to a lesser extent in sham rats but not in naive rats. In the presence of gabapentin (ineffective low dose of 10 mg/kg), morphine (1 and 3 mg/kg) mediated significant inhibitory effects in all experimental groups, with the greatest inhibitions observed in spinal nerve-ligated and sham-operated rats. After neuropathy, inhibitions mediated by morphine were significantly increased in the presence of gabapentin compared with morphine alone. CONCLUSIONS: After spinal nerve ligation, the inhibitory effects of systemic morphine on evoked dorsal horn neuronal responses are reduced compared with control, whereas the effectiveness of systemic gabapentin is enhanced. In combination with low-dose gabapentin, significant improvement in the effectiveness of morphine is observed, which demonstrates a clinical potential for the use of morphine and gabapentin combinational treatment for neuropathic pain.

Acetates↗
PubMed2000

Effects of midazolam in the spinal nerve ligation model of neuropathic pain in rats.

Potential changes in the spinal GABAergic activity after nerve injury were studied by comparing the effects of systemic administration of the benzodiazepine midazolam on the noxious evoked responses of dorsal horn in rats with spinal nerve ligation of neuropathy and control animals. The tight ligation of the L(5) and L6 spinal nerves was performed in adult male Sprague-Dawley rats and resulting mechanical and cold allodynia were assessed with von Frey hairs and the acetone drop test. Single unit extracellular recordings of dorsal horn neurones were performed 15-18 days after the surgery under halothane anaesthesia using transcutaneous electrical stimulation of the receptive field at three times the C-fibre threshold. The rats in the spinal nerve ligation group, but not in the sham-operated control group developed mechanical and cold allodynia. Subcutaneous administration of midazolam 0.1-3.0 mg/kg reduced the Adelta-fibre evoked activity in a dose-related manner in all study groups, but the C-fibre evoked activity was significantly reduced only in the spinal nerve ligation group. The inhibitory effects of s.c. midazolam were significantly reversed by i.t. administration of flumazenil, suggesting a spinal site of action. Midazolam reduced C-fibre evoked firing significantly more in the spinal nerve ligation model than in the non-operated or sham controls. These results indicate changes in the spinal GABAergic system in the neuropathic animals and could be of importance in the development of new treatments for neuropathic pain.

Animals↗
PubMed2000

Unaltered peripheral excitatory actions of nociceptin contrast with enhanced spinal inhibitory effects after carrageenan inflammation: an electrophysiological study in the rat.

Nociceptin (orphanin FQ) is the endogenous agonist of the opioid receptor-like (ORL-1) receptor. The actions of this peptide have been studied extensively at a number of sites with diverse actions being reported. Here, in a rat model of peripheral inflammation, we examine the effects of nociceptin on the responses of dorsal horn neurones when applied directly to the spinal cord and, in separate studies, into the peripheral receptive fields in the hindpaw of the halothane anaesthetized rat. As changes in the receptor density and expression of the message for nociceptin have been reported after inflammation we have compared these actions to previously reported effects in normal animals. The dose-dependent inhibitory actions of nociceptin on C-fibre evoked responses and input (measures of presumed pre-synaptic excitability) are increased 3-4 h after inflammation whereas its inhibitory effects on post-synaptic mechanisms (wind-up) remain unchanged. These inhibitory effects were partly reversible by high doses of naloxone. This increased potency of nociceptin after inflammation is consistent with an increased receptor density in the superficial spinal cord. In contrast, the peripheral administration of nociceptin produced dose-dependent excitations of dorsal horn neurones and a degree of sensitization to mechanical stimuli. This peripheral action was unchanged after inflammation. These diverse site-dependent actions of nociceptin further emphasize the complexities of this novel opioid system.

Animals↗
PubMed1998

A novel spinal action of mexiletine in spinal somatosensory transmission of nerve injured rats.

Mexiletine is widely used for the treatment of neuropathic pain although its site(s) of action remain unclear. Here we have studied the effect of spinal administration of mexiletine (10-1000 microg) on the spontaneous and peripherally evoked responses of spinal neurones of nerve injured (selective ligation of spinal nerves L5-L6; SNL) rats. Sham controls for the surgical intervention were performed. A high proportion of the spinal neurones of SNL rats exhibited de novo spontaneous activity (mean frequency of firing 4+/-1 Hz), this activity was highly sensitive to spinal mexiletine (F5,55 = 2.5, P < or = 0.05). The spinal neurones of the sham operated rats exhibited negligible spontaneous activity. The electrically evoked Abeta-fibre neuronal responses of SNL and sham operated rats were not significantly influenced by spinal mexiletine. In contrast, the Adelta-fibre and C-fibre evoked neuronal responses of the SNL rats, but not sham operated rats, were significantly reduced by spinal mexiletine (F5.52 = 4.9, P < or = 0.001 and F5,48 = 12, P < or = 0.0001, respectively). In addition, the mechanical punctate von Frey 9 and 50 g evoked neuronal responses of the SNL rats, but not sham operated rats, were significantly reduced by spinal mexiletine (F5,57 = 4.3, P < or = 0.002 and F5,52 = 6.1, P < or = 0.001). This pharmacological study suggests that following nerve injury there is a novel mexiletine sensitive spinal substrate which contributes to Adelta-fibre and C-fibre, but not Abeta-fibre, somatosensory transmission. This central action may underlie some of the clinical efficacy of mexiletine in the treatment of neuropathic pain states.

Animals↗
PubMed1994

Electrophysiological studies on the spinal roles of endogenous opioids in carrageenan inflammation.

This electrophysiological study uses the mixed peptidase inhibitor kelatorphan and the selective kappa-antagonist nor-binaltorphimine (nor-BNI) to investigate whether there is altered modulation of spinal nociceptive transmission by endogenous opioids 3 h after injection of carrageenan into the ipsilateral paw. Intrathecal kelatorphan (5-250 micrograms) inhibited the C-fibre evoked response of dorsal horn neurones in both normal and carrageenan animals, with no difference in this inhibitory effect found between the 2 groups of animals. In both groups of animals, this inhibition reached a plateau at 50%. Thus there was no change in the effects exerted by the spinal enkephalins at this point in the inflammatory state. Nor-BNI (10 and 100 micrograms) produced a bidirectional change in the C-fibre evoked response of dorsal horn neurones in both normal and carrageenan animals, facilitating the evoked response of some neurones whilst inhibiting others. The magnitude of the change in the neuronal response induced by nor-BNI in carrageenan animals was significantly greater than that seen in normal animals, suggesting a greater release of spinal dynorphin in the inflammatory state. Dorsal horn neurones showed a bidirectional change in response as carrageenan-induced inflammation developed, although the direction of this change did not correlate with the subsequent direction of effect of nor-BNI. There was, however, a significant correlation between the magnitude of the change in the C-fibre evoked response after the injection of carrageenan and the magnitude of change produced in the same cells by nor-BNI.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1993

Lack of effect of morphine-3-glucuronide on the spinal antinociceptive actions of morphine in the rat: an electrophysiological study.

Previous studies have shown that morphine-3-glucuronide (M3G), a metabolite of morphine, may functionally antagonize the antinociceptive action of morphine. The interaction between morphine and M3G was therefore investigated in the halothane-anaesthetised rat. Extracellular unit recordings were made of the innocuous A-beta fibre and noxious C-fibre evoked responses of convergent dorsal horn neurones. Intrathecal M3G (5 micrograms, 100 micrograms and 500 micrograms) alone did not show any antinociceptive effect. There was a slight, but not statistically significant, decrease in the antinociceptive effect of 5 micrograms morphine in the M3G-pretreated groups. However, M3G pretreatment (5 micrograms, 100 micrograms and 500 micrograms) had no effect on the higher dose of morphine (50 micrograms) used. We conclude that M3G has, at most, a minor effect on the spinal antinociceptive effects of morphine.

Analgesics↗
PubMed1992

Alterations in neuronal excitability and the potency of spinal mu, delta and kappa opioids after carrageenan-induced inflammation.

These electrophysiological results show that the development of inflammation following peripheral injection of carrageenan into the paw is accompanied by alterations in the magnitude of the C-fibre evoked response of multireceptive dorsal horn neurones. The evoked response of the dorsal horn cells was found to either increase or decrease in the 3 h following the carrageenan injection, and the direction of this change was related to the degree of wind-up exhibited by the cell. Regardless of whether a cell was facilitated or inhibited by carrageenan, mu, delta and kappa opioids applied topically onto the spinal cord (equivalent to an intrathecal injection) exhibited increased antinociceptive potency. This increased effectiveness was especially marked for the mu opioid, morphine, which showed a 30-fold increase in potency. Interestingly the facilitations seen with the lowest doses of the mu and kappa opioids in this model in normal animals were absent after carrageenan. In addition, a very low dose of spinal naloxone caused a small but significant reduction in the C-fibre evoked responses. These results demonstrate that following peripheral inflammation, functional changes develop in both spinal transmission and modulatory systems. Alterations in the antinociceptive potency of opioid agonists occurs, with the mu agonist, morphine, showing the greatest change.

Animals↗
PubMed1992

Spinal local anaesthetic actions on afferent evoked responses and wind-up of nociceptive neurones in the rat spinal cord: combination with morphine produces marked potentiation of antinociception.

Lignocaine was tested either alone or in combination with a low dose of morphine by intrathecal administration on the C- and A-beta evoked responses of nociceptive neurones in the dorsal horn of the halothane-anaesthetized rat. In addition the effect of prilocaine was compared to lignocaine. The effects of lignocaine on wind-up, a frequency-dependent increase in the responses of the cells produced by repeated C-fibre stimulation was also tested. Lignocaine produced dose-dependent inhibitions of the C-, A-delta and A-beta evoked responses of the cells which became more selective for the noxious evoked responses as the dose increased. The effective doses corresponded well to those used clinically. Wind-up was also decreased by lignocaine. In combination with a low dose of morphine, threshold doses of lignocaine produced a highly marked potentiation of the inhibitions of the C-fibre evoked responses compared to either agent alone. No potentiation of the inhibitions of the A-beta responses was observed. The potentiated inhibitory effects on the C-fibre responses were rapidly reversed by intrathecal naloxone. The finding that spinal local anaesthetic and morphine potentiate markedly to reduce spinal nociception is discussed both in terms of mechanisms of action of the agents and their clinical application.

Afferent Pathways↗
PubMed1989

Electrophysiological studies on the effects of opiates on dorsal horn nociceptive neurones at 51 atmospheres absolute.

The purpose of this study was to investigate the effects, if any, of high pressure on opiate analgesia. The interaction of high pressure with intrathecal morphine (2.5-15 micrograms) and pethidine (10-145 micrograms) was studied on the responses of 51 dorsal horn neurones in the intact rat under urethane anaesthesia to electrical stimulation applied to their receptive fields. Two types of response to the addition of the opiates were found. Cells were either rapidly and maximally inhibited by the lowest dose of morphine (2.5 micrograms) or pethidine (10 micrograms) or slowly inhibited in a dose-dependent manner with an ED50 of 13.6 nmol for morphine and 401 nmol for pethidine. Pressure did not significantly affect the time-response curves for these two types of response but did change the relative numbers of each type recorded. The number of cells totally inhibited by the lowest of drug concentrations was increased for morphine at pressure but decreased for pethidine.

Action Potentials↗
PubMed1989

Intrathecal opioids, potency and lipophilicity.

To determine the relationship between potency and lipophilicity for intrathecal opioids, morphine, normorphine, pethidine and methadone were studied in an electrophysiological model in the rat. Dose-response curves were constructed for the opioid effects on C fibre evoked activity of dorsal horn nociceptive neurones following intrathecal application of each opioid, and the ED50 values were correlated with lipid solubility. A significant inverse correlation was found (P = 0.002; r = 0.998) so that the most lipid soluble drugs were the least potent. The possible mechanism of this relationship, the implications for spinal opioid use and the effect of different administration routes on the relationship between lipid solubility and potency are considered.

Action Potentials↗
PubMed1987

Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin.

Many studies of pain and nociception use short-lasting acute stimuli which may have limited relevance to prolonged or chronic pain states. Using extracellular single-unit recording in the dorsal horn of the rat lumbar spinal cord the present study examines the response of neurones to a long-lasting nociceptive stimulus, i.e., 50 microliter 5% formalin injected into the corresponding receptive field in the ipsilateral hind paw, and modulation of this response by an opioid. Formalin produced a distinct biphasic excitatory response in all convergent neurones tested; an immediate acute or phasic peak of neuronal firing (mean maximum 22 spikes/sec) 0-10 min post injection, and a second more prolonged tonic excitatory response (mean maximum 12 spikes/sec) over a period 20-65 min after formalin. Cells only activated by innocuous stimuli were not excited by formalin indicating the involvement of C fibre afferents in the excitatory response of convergent neurones to formalin. Both the biphasic nature and the time course of the neuronal response are similar to those observed in behavioural studies. Intrathecal DAGO (Tyr-D-AlaGlyMePheGly-ol), a potent and selective mu opioid receptor agonist, applied 20 min prior to formalin completely inhibited both peaks of excitation. Co-administration of intrathecal naloxone with the agonist restored the biphasic response. By contrast, when the administration of naloxone was delayed to 2 min post formalin so that inhibition of the first peak by DAGO pretreatment occurred, there was no subsequent second peak of activity although antagonism of the opioid would have occurred. When DAGO was applied 2 min post formalin so the initial acute response occurred, the inhibitory effect of the agonist on the second peak was far less. Thus the relative ability of DAGO to modulate the biphasic excitatory response of cells to formalin depends on whether the agonist is administered prior to or after the formalin and the appearance of the second peak may depend on the presence of the first. These results are discussed in light of the role of these neurones in nociception, opioid effects and changes in neural systems following peripheral stimuli.

Animals↗
PubMed1986

Electrophysiological studies on the effects of intrathecal morphine on nociceptive neurones in the rat dorsal horn.

We have studied the effects of intrathecal morphine on the responses of 38 dorsal horn neurones in the intact rat under halothane anaesthesia to A and C fibre electrical stimulation and to natural stimuli applied to their receptive fields. Morphine selectively reduced the C fibre and pinch evoked activity in a dose-dependent naloxone-reversible manner with an ED50 of 7 nmoles. The 'wind-up' of neurones to repetitive stimulation was little altered except with the highest doses (50-150 nmoles) tested. By contrast, the A fibre evoked responses of the neurones were only slightly reduced by morphine and both the tactile responses and receptive field size to innocuous stimuli enhanced for certain cells. The results are discussed in relation to the spinal actions of opiates and their clinical applications.

Animals↗
PubMed1979

Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.

(1) Sixty-eight convergent dorsal horn neurones have been recorded at the lumbar level in anaesthetized intact rats. All cells received prominent A alpha and C fibre afferents and correspondingly could be activated by high and low threshold stimuli applied to the peripheral excitatory receptive field. (2) The activity of 67/68 of these neurones was powerfully inhibited by noxious stimuli applied to various parts of the body. Since non-noxious stimuli were ineffective in this respect, the term "diffuse noxious inhibitory controls" (DNIC) is proposed. (3) DNIC could be evoked by noxious pinch applied to the tail, the contralateral hind paw, the forepaws, the ears and the muzzle; the most effective areas were the tail and muzzle. Noxious heat applied to and transcutaneous electrical stimulation of the tail were extemely effective in eliciting DNIC as was the intraperitoneal injection of bradykinin. (4) DNIC strongly depressed by 60-100% both the C fibre response following suprathreshold transcutaneous electrical stimulation and the responses to noxious radiant heat. (5) The spontaneous activity and the responses to low threshold afferents induced either by A alpha threshold electrical or natural stimulation were also powerfully inhibited. (6) In the majority of cases, long lasting post-effects directly related to the duration of conditioning painful stimulus were observed.

Animals↗
PubMed1979

Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications.

(1) Diffuse noxious inhibitory controls (DNIC) were tested for their effect on noxious only, non-noxious and proprioceptive cells in the dorsal horn of the intact anaesthetized rat. Unlike convergent neurones, as described in the previous paper, there was no effect of DNIC on these neurones. It is concluded that convergent neurones are specifically inhibited by DNIC. (2) The effect of DNIC could not be demonstrated for convergent neurones in the spinal animal. Thus the neuronal substrate for DNIC must involve supraspinal structures. (3) Because of the level of firing in convergent neurones induced by hair and touch receptors, presumably constantly and randomly activated in the freely moving animal, a noxious message arriving at higher centres may be partly masked by this background noise. On the basis of the known role of convergent neurones in nociception, we propose the following mechanism which may interpret this paradoxical convergence: two pools of convergent neurones are influenced by a painful peripheral stimulation, one segmental pool being activated whilst the remaining population of cells is inhibited; the "contrast" between the messages from these two pools may well produce a significant pain signalling output from the convergent dorsal horn cells. (4) These results and their theoretical implications are discussed with regard to the concept of the "analgesic system", certain clinical observations and the paradoxical pain relieving effects of counterirritation and some forms of acupuncture.

Acupuncture Therapy↗