Papers by Mike Cumberbatch
SIGLEAvailable from British Library Document Supply Centre- DSC:DX184351 / BLDSC - British Librar... more SIGLEAvailable from British Library Document Supply Centre- DSC:DX184351 / BLDSC - British Library Document Supply CentreGBUnited Kingdo
Neuropharmacology, 1998
In adult rats response latencies to innocuous mechanical stimuli were found to be reduced and, in... more In adult rats response latencies to innocuous mechanical stimuli were found to be reduced and, in electrophysiological studies, the receptive fields of dorsal horn neurones were enlarged 7-14 days after chronic constriction injury of the sciatic nerve. The NK 1 receptor antagonist GR205171 at 3 mg kg − 1 blocked responses to NK 1 agonist evoked activity and reversed the mechanical hypersensitivity following nerve ligation in behavioural assays. GR205171 also reversed the receptive field expansion of spinal dorsal horn neurones caused by loose ligation of the sciatic nerve in an electrophysiological assay in anaesthetised rats. The less active enantiomer L-796,325 did not block NK 1 agonist evoked activity at up to 10 mg kg − 1 and had no effect on behavioural or electrophysiological changes following nerve injury, indicating that the effects of GR205171 were attributable to selective NK 1 receptor blockade. These data suggest that NK 1 receptor antagonists may be useful for the treatment of certain types of neuropathic pain.
European Journal of Pharmacology, 1998
Pre-clinical studies have suggested that one mechanism of antimigraine action of the 'tri... more Pre-clinical studies have suggested that one mechanism of antimigraine action of the 'triptan' 5-HT1B/1D receptor agonists may be through inhibition of central nociceptive transmission in the trigeminal dorsal horn. In anaesthetized rats, the 5-HT1B/1D receptor agonist, zolmitriptan (up to 3 mg kg(-1), i.v.), inhibited the action potential discharge of single trigeminal neurones to noxious electrical stimulation of the middle meningeal artery. In contrast, the selective 5-HT1B receptor agonist, CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one), and the 5-HT1A receptor selective agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) had no effect in this assay at up to 3 mg kg(-1), i.v.. Brain penetrant, triptan 5-HT1B/1D receptor agonists may therefore mediate their central trigeminal anti-nociceptive action in the rat via 5-HT1D, but not 5-HT1B or 5-HT1A, receptors.
European Journal of Pharmacology, 1997
The 5-HT receptor agonist rizatriptan constricts intracranial, extracerebral blood vessels, inhib... more The 5-HT receptor agonist rizatriptan constricts intracranial, extracerebral blood vessels, inhibits neurogenic vasodilation and 1Br1D extravasation in the meninges and is effective clinically against migraine. The present study has investigated whether rizatriptan may also Ž. have activity at 5-HT receptors within the central nervous system CNS that contributes to its antimigraine effects. Action 1Br1D potentials evoked by electrical stimulation of the dura-mater were recorded extracellularly from single neurones in the trigeminal nucleus caudalis in anaesthetized rats. Rizatriptan dose dependently inhibited these nociceptive dural responses by up to 63 " 9% after 3 mgrkg, i.v. Rizatriptan therefore has central activity which may contribute to its efficacy against migraine headache.
Neuroscience Letters, 1994
The ability of excitatory amino acids (EAAs) to modulate nociceptive and non-nociceptive response... more The ability of excitatory amino acids (EAAs) to modulate nociceptive and non-nociceptive responses was tested on spinal neurones of the anaesthetized rat. NMDA (N-methyl-D-aspartate), AMPA ((RS)-~-amino-3-hydroxy-5-methyl-4-isoxazole-propionate) and kainate were applied by iontophoretic ejection to increase .the background firing rate of each cell to ~25 spikes/s. Responses to noxious heat and pinch and innocuous tap stimuli were enhanced to similar degrees by all three EAAs and returned to control immediately following termination of EAA ejection. This result shows that, whilst NMDA does enhance synaptic responses of spinal neurones, this effect is little or no greater than for AMPA or kainate. Furthermore, the rapid recovery of nociceptive responses indicates that more than NMDA receptor activation alone is required to induce longer-term enhancement of nociceptive responses (hyperalgesia).
represent a novel mechanistic approach to antidepressant therapy with comparable clinical efficac... more represent a novel mechanistic approach to antidepressant therapy with comparable clinical efficacy to selective serotonin reuptake inhibitors (SSRIs). Because SSRIs are thought to exert their therapeutic effects by enhancing central serotonergic function, we have examined whether SPAs regulate neuronal activity in the dorsal raphe nucleus (DRN), the main source of serotonergic projections to the forebrain. Using in vivo electrophysiological techniques in the guinea pig, we found that administration of the highly selective NK 1 receptor antagonist
Drug Treatment of Migraine and Other Headaches, 2000
The Journal of Physiology, Dec 1, 1996
Journal of Neurology, Neurosurgery & Psychiatry
Neuroscience, 2002
The mechanism of action of conventional antidepressants (e.g. imipramine) has been linked to modu... more The mechanism of action of conventional antidepressants (e.g. imipramine) has been linked to modulation of central monoamine systems. Substance P (NK1) receptor antagonists may have antidepressant and anxiolytic effects in patients with major depressive disorder and high anxiety but, unlike conventional antidepressants, are independent of activity at monoamine reuptake sites, transporters, receptors, or monoamine oxidase. To investigate the possibility that substance P receptor antagonists influence central monoamine systems indirectly, we have compared the effects of chronic administration of imipramine with that of the substance P receptor antagonist L-760735 on the spontaneous firing activity of locus coeruleus neurones. Electrophysiological recordings were made from brain slices prepared from guinea-pigs that had been dosed orally every day for 4 weeks with either L-760735 (3 mg/kg), imipramine (10 mg/kg), or vehicle (water), or naive animals. Chronic, but not acute, treatment w...
Neuropharmacology, Jan 14, 2000
The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (... more The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets. In a 4 h observation period, MK-0869 and L-758,298 (3 mg/kg i.v. or p.o.) inhibited the emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection afforded by MK-0869 (0.1 mg/kg i.v.) was enhanced by combined treatment with either dexamethasone (20 mg/kg i.v.) or the 5-HT3 receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment with MK-0869 (4-16 mg/kg p.o.) dose-dependently inhibited the emetic response to cisplatin. Once daily treatment with MK-0869 (2 and 4 mg/kg p.o.) completely prev...
Journal of Neuroimmunology, 2014
NMDA Antagonists as Potential Analgesic Drugs, 2002
The excitatory amino acids, glutamate and aspartate, have long been recognised as being fundament... more The excitatory amino acids, glutamate and aspartate, have long been recognised as being fundamental to the processing of nociceptive and non-nociceptive information in the spinal cord (for review see [1]). Both of these neurotransmitters are released into the dorsal horn following noxious peripheral stimulation [2]. In the early 1960s it was found that glutamate and aspartate strongly excited spinal neurones [3] and that various analogues of these amino acids were also potently active. Amongst these was NMDA [4]. It was proposed that, based upon the differential potencies of various excitant amino acids on different types of spinal neurones, a specific NMDA sensitive site existed [5, 6]. It was also found that Mg2+ could selectively inhibit responses to NMDA in the spinal cord [7] which has led to the current understanding of the voltage dependent Mg2+ block of the NMDA receptor [8]. Since these early experiments the NMDA receptor has been extensively characterised and molecular cloning techniques have revealed a variety of subunits that have a differential distribution throughout the central nervous system.
Neuroscience Letters, 1996
Studies of synaptic transmission in vivo: indirect versus direct effects of (RS)-a-amino-3-hydrox... more Studies of synaptic transmission in vivo: indirect versus direct effects of (RS)-a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid/kainate antagonists on rat spinal sensory responses
Neuroscience, 1997
The importance of receptors for N-methyl-D-aspartate in synaptic plasticity and in triggering lon... more The importance of receptors for N-methyl-D-aspartate in synaptic plasticity and in triggering long-term pronociceptive changes is explained by their voltage-dependence. This suggests that their contribution to acute nociceptive responses would be determined both by the magnitude of synaptic input and by the level of background excitation. We have now examined the role of N-methyl-D-aspartate receptors in acute nociceptive transmission in the spinal cord. Drugs selectively affecting activity mediated by these receptors were tested on responses of dorsal horn neurons to noxious stimuli of different intensities and at different levels of ongoing spike discharge. The drugs used were the N-methyl-D-aspartate receptor channel blocker ketamine; the competitive antagonists, 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (D-CPP) and D-2-amino-5-phosphonopentanoic acid (D-AP5), and the positive modulator thyrotropin-releasing hormone. The activity of dorsal horn wide dynamic range neurons was recorded extracellularly in alpha-chloralose-anaesthetized spinalized rats. Their responses to noxious stimuli (pinch, heat and electrical) were monitored in parallel with responses to iontophoretic N-methyl-D-aspartate and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA). Drugs were given i.v. or (D-AP5) iontophoretically. At doses that selectively inhibited responses to exogenous N-methyl-D-aspartate, ketamine (4 or 8, mean 5 mg/kg i.v.) reduced the nociceptive responses of the majority of the cells in deep dorsal horn. Ketamine also reduced wind-up of the responses to repetitive electrical stimulation. Ketamine (4 or 8 mg/kg). D-CPP (2 mg/kg), D-AP5 (iontophoretically) and thyrotrophin-releasing hormone (1 mg/kg) were tested on different magnitude nociceptive responses evoked by alternating intensities of noxious heat or pinch. In percentage terms, the less vigorous responses were affected by all four drugs as much as or more than the more vigorous responses. When background activity of neurones was enhanced by continuous activation of C-fibres with cutaneous application of mustard oil, ketamine was less effective against superimposed noxious pinch responses. Ongoing background activity was affected in parallel with evoked responses. When background discharge of the cells was maintained at a stable level with continuous ejection of kainate, neither the N-methyl-D-aspartate antagonists nor thyrotrophin-relasing hormone affected the responses to noxious pinch or heat, although responses to exogenous N-methyl-D-aspartate were still blocked. The wind-up of the electrical responses was, however, reduced by ketamine irrespective of the level of background activity. The results indicate that under these conditions in vivo, N-methyl-D-aspartate receptors mediate ongoing low-frequency background activity rather than phasic high-frequency nociceptive responses. The effects of N-methyl-D-aspartate antagonists and positive modulators on nociceptive responses are evidently indirect, being secondary to changes in background synaptic excitation. These results cannot be explained simply in relation to the voltage-dependence of N-methyl-D-aspartate receptor-mediated activity; other factors, such as modulation by neuropeptides, must be involved.
NeuroReport, 1994
The relative roles of receptors for AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic aci... more The relative roles of receptors for AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) in spinal nociceptive and non-nociceptive transmission were studied on dorsal horn wide dynamic range neurones in alpha-chloralose-anaesthetized spinalized rats. The effects of systemically administered competitive and non-competitive AMPA antagonists (the quinoxalinedione NBQX and the 2,3-benzodiazepine GYKI 53655) were examined on responses to peripheral noxious heat and non-noxious tap stimuli as well as to iontophoretic AMPA and N-methyl-D-aspartate (NMDA). Both NBQX and GYKI 53655 dose-dependently reduced responses to peripheral stimuli and to AMPA. GYKI 53655, the more selective antagonist of AMPA vs NMDA, decreased heat and tap responses to the same extent. The results indicate that AMPA receptors play a significant and equal, but not exclusive, role in mediating nociceptive and non-nociceptive spinal transmission.
Cephalalgia, 1999
This study investigated whether the selective 5HT1F receptor agonist LY334370 has other possible ... more This study investigated whether the selective 5HT1F receptor agonist LY334370 has other possible antimigraine mechanisms in addition to the proposed inhibition of dural plasma extravasation. LY334370 (up to 10−5 M) had no vasoconstrictor effects on human cerebral arteries in vitro. It had no effect (up to 10 mg kg−1, iv) on neurogenic vasodilation of dural blood vessels produced by electrical stimulation of the dura mater in anesthetized rats. Nor had it any effect (at 3 mg kg−1, iv) on the hyperalgesia produced by injection of carrageenan into the paw of conscious rats or on nociceptive reflex responses in the spinalized, decerebrate rabbit (up to 3 mg kg−1, iv), indicating that it has no general analgesic properties. However, it significantly inhibited activation of second-order neurons in the trigeminal nucleus caudalis produced by electrical stimulation of the dura mater in anesthetised rats at 3 mg kg−1, iv. These results provide evidence to suggest that LY334370 has a central ...
Cephalalgia, 1998
In vivo electrophysiological assays in anesthetized rats have been used to compare the effects of... more In vivo electrophysiological assays in anesthetized rats have been used to compare the effects of the 5HT1B/1D receptor agonist, naratriptan, on central trigeminal nociceptive processing from dural and cutaneous inputs with its effects on nociceptive processing in the spinal cord. Naratriptan inhibited responses of single trigeminal neurons, to noxious electrical and mechanical stimulation of the dura and face, dose dependently by a maximum of 67+/-3% and 70+/-18%, respectively, at 3 mg kg(-1) i.v. In contrast, naratriptan did not affect spinal dorsal horn neuronal responses to noxious mechanical stimulation of the hind-paw. These findings suggest that 5HT1B/1D receptors have differential effects on nociceptive processing in the trigeminal versus spinal dorsal horns and provide a potential explanation for the lack of general analgesic effects of brain penetrant 5HT(1B/1D) agonist antimigraine drugs.
British Journal of Pharmacology, 1999
Migraine headache pain is thought to result from an abnormal distention of intracranial, extracer... more Migraine headache pain is thought to result from an abnormal distention of intracranial, extracerebral blood vessels and the consequent activation of the trigeminal nervous system. Migraine is also often accompanied by extracranial sensory disturbances from facial tissues. These experiments investigate whether meningeal dilation produces central sensitization of neurones that receive convergent input from the face. 2 Single unit extracellular activity was recorded from the trigeminal nucleus caudalis of anaesthetized rats in response to either noxious stimulation of the dura mater, innocuous stimulation of the vibrissae or to a transient dilation of the meningeal vascular bed. 3 Rat a-CGRP (calcitonin gene-related peptide; 1 mg kg 71 , i.v.) caused a dilation of the middle meningeal artery and facilitated vibrissal responses by 36+7%. 4 The 5-HT 1B/1D agonist, L-741,604 (3 mg kg 71 , i.v.), inhibited responses to noxious stimulation of the dura mater (16+7% of control) and, in a separate group of animals, blocked the CGRP-evoked facilitation of vibrissal responses. 5 L-741,604 (3 mg kg 71 , i.v.) also inhibited responses to innocuous stimulation of the vibrissa (14+10% of control) with neurones that received convergent input from the face and from the dura mater, but not with cells that received input only from the face (70+12% of control). 6 These data show that dilation of meningeal blood vessels causes a sensitization of central trigeminal neurones and a facilitation of facial sensory processing which was blocked by activation of pre-synaptic 5-HT 1B/1D receptors. 7 Sustained dural blood vessel dilation during migraine may cause a sensitization of trigeminal neurones. This may underlie some of the symptoms of migraine, such as the headache pain and the extracranial allodynia. Inhibition of this central sensitization may therefore oer a novel strategy for the development of acute and/or prophylactic anti-migraine therapies.
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Papers by Mike Cumberbatch