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1.
Mol Cell Neurosci ; 30(4): 523-37, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16202621

ABSTRACT

Activation of intracellular signaling pathways involving p38 and p42/44 MAP kinases may contribute importantly to synaptic plasticity underlying spinal neuronal sensitization. Inhibitors of p38 or p42/44 pathways moderately attenuated responses of dorsal horn neurons evoked by mustard oil but not brush and alleviated the behavioral reflex sensitization seen following nerve injury. Activation of p38 and p42/44 MAP kinases in spinal cord ipsilateral to constriction injury was reduced by antagonists of NMDA, VPAC2 and NK2 (but not related) receptors, the glial inhibitor propentofylline and inhibitors of TNF-alpha. A VPAC2 receptor agonist enhanced p38 phosphorylation and caused behavioral reflex sensitization in naïve animals that could be blocked by co-administration of p38 inhibitor. Conversely, an NK2 receptor agonist activated p42/44 and caused behavioral sensitization that could be prevented by co-administration of p42/44 inhibitor. Thus, spinal p38 and p42/44 MAP kinases are activated in neuropathic pain states by mechanisms involving VPAC2, NK2, NMDA receptors and glial cytokine production.


Subject(s)
MAP Kinase Signaling System/physiology , Neuroglia/metabolism , Peripheral Nervous System Diseases/metabolism , Posterior Horn Cells/metabolism , Receptors, Neurokinin-2/metabolism , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Animals , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Activation/physiology , Enzyme Inhibitors/pharmacology , Inflammation Mediators/pharmacology , MAP Kinase Signaling System/drug effects , Male , Mitogen-Activated Protein Kinase 1/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Neuralgia/metabolism , Neuralgia/physiopathology , Neuroglia/drug effects , Neuroprotective Agents/pharmacology , Peripheral Nerve Injuries , Peripheral Nerves/metabolism , Peripheral Nerves/physiopathology , Peripheral Nervous System Diseases/physiopathology , Phosphorylation/drug effects , Physical Stimulation , Posterior Horn Cells/drug effects , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, Neurokinin-2/drug effects , Receptors, Vasoactive Intestinal Peptide, Type II/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Xanthines/pharmacology , p38 Mitogen-Activated Protein Kinases/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism
2.
Curr Pharm Des ; 11(23): 2961-76, 2005.
Article in English | MEDLINE | ID: mdl-16178756

ABSTRACT

Neuropathic pain is characterised by both positive (hyperalgesia and allodynia) and negative (sensory deficits) symptoms and remains intractable to many commonly used analgesics. Antiepileptics are increasingly utilised in the treatment of neuropathic pain. This class of drugs works via three major mechanisms of action in order to dampen neuronal hyperexcitability within the central nervous system: potentiation of GABA transmission, reduction of glutamate-mediated excitatory transmission, and block of voltage-activated ion channels. The latter mechanism of action in particular, is exemplified by the success of the newer generation of antiepileptics such as lamotrigine and gabapentin in the clinical treatment of neuropathic pain symptoms. In the current review article, we will examine in detail, the antinociceptive effects of a diverse range of antiepileptics as tested in animal models of nerve injury. Where appropriate, we will compare these findings with their analgesic efficacy in the clinical treatment of neuropathic pain.


Subject(s)
Anticonvulsants/therapeutic use , Pain/drug therapy , Peripheral Nervous System Diseases/drug therapy , Animals , Disease Models, Animal , Humans , Neurons, Afferent/drug effects , Neurons, Afferent/physiology , Pain/etiology , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/physiopathology
3.
CNS Drug Rev ; 11(1): 1-20, 2005.
Article in English | MEDLINE | ID: mdl-15867950

ABSTRACT

Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.


Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/therapeutic use , Carbamates/chemical synthesis , Carbamates/therapeutic use , Epilepsy/drug therapy , Phenylenediamines/chemical synthesis , Phenylenediamines/therapeutic use , Animals , Anticonvulsants/pharmacokinetics , Anxiety/drug therapy , Carbamates/pharmacokinetics , Dose-Response Relationship, Drug , Humans , KCNQ Potassium Channels , KCNQ1 Potassium Channel , Neurons/drug effects , Neurons/physiology , Pain/drug therapy , Phenylenediamines/pharmacokinetics , Potassium Channels, Voltage-Gated/drug effects , Time Factors
4.
J Neuroendocrinol ; 13(12): 1009-23, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11722697

ABSTRACT

Chronic pain and depressive illness are debilitating disease states that are variably resistant to currently available therapeutic agents. Animal models of chronic pain are associated with activation of the hypothalamo-pituitary-adrenal (HPA) axis, upon which chronic pain acts as an inescapable stressor. Inescapable stress is also associated with 'depressive-like' symptoms in experimental animals. Based on reports of the comorbidity between chronic pain and depressive illness in human patients, it is possible that these disease states are linked, via chronic stress-induced HPA dysfunction. Here, we discuss the possible involvement of the HPA axis in the aetiology of both chronic pain and clinical depression, and suggest a strategy for the development of novel pharmacotherapies.


Subject(s)
Depression/etiology , Pain/complications , Pain/psychology , Stress, Physiological/etiology , Animals , Chronic Disease , Depression/physiopathology , Humans , Hypothalamo-Hypophyseal System/physiology , Pain/physiopathology , Pituitary-Adrenal System/physiology , Stress, Physiological/physiopathology
5.
Neurosci Res ; 39(4): 385-90, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11274737

ABSTRACT

Some opioid-resistant pain conditions can be alleviated by voltage-dependent Na(+) channel blockers such as lamotrigine. The mu-opioid-receptor agonist morphine can modulate cation entry into cells to affect overall cellular excitability, an effect which can in turn be endogenously antagonised by the neuropeptide cholecystokinin (CCK). However, lamotrigine may also modulate cellular excitability by non-specifically blocking voltage-dependent ion channels. We have looked for interactions of lamotrigine with the opioid/CCK pathway within the spinal dorsal horn, to rule out the possibility that lamotrigine may attenuate nociceptive responses via actions on this pathway. Both lamotrigine and the mu-opioid agonist DAMGO inhibited mustard oil-evoked cell firing by approximately 50% compared with control levels. Co-application of CCK8S reversed DAMGO-, but not lamotrigine-induced inhibition of cell firing and this reversal was prevented with the selective CCK(B) receptor antagonist PD 135158. Although lamotrigine inhibited both brush- and cold-evoked cell firing in neuropathic animals, lamotrigine inhibition of mustard oil-evoked cell firing in the same animals was not significantly greater than that observed in controls. These results suggest that the antinociceptive properties of lamotrigine within the spinal dorsal horn are unlikely to be mediated via interactions with the opioid/CCK pathway.


Subject(s)
Calcium Channel Blockers/pharmacology , Neural Pathways/drug effects , Nociceptors/drug effects , Opioid Peptides/metabolism , Pain/drug therapy , Posterior Horn Cells/drug effects , Triazines/pharmacology , Action Potentials/drug effects , Action Potentials/physiology , Analgesics, Opioid/pharmacology , Animals , Anti-Anxiety Agents/pharmacology , Cholecystokinin/metabolism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Indoles/pharmacology , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/physiopathology , Lamotrigine , Male , Meglumine/analogs & derivatives , Meglumine/pharmacology , Mustard Plant , Neural Pathways/cytology , Neural Pathways/metabolism , Nociceptors/cytology , Nociceptors/metabolism , Pain/metabolism , Pain/physiopathology , Peripheral Nervous System Diseases/drug therapy , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/physiopathology , Plant Extracts/pharmacology , Plant Oils , Posterior Horn Cells/cytology , Posterior Horn Cells/metabolism , Rats , Rats, Wistar , Sincalide/pharmacology
6.
Neuropharmacology ; 39(9): 1596-607, 2000 Jul 10.
Article in English | MEDLINE | ID: mdl-10854904

ABSTRACT

We investigated whether the full expression of morphine withdrawal excitation by supraoptic nucleus (SON) oxytocin neurones is a property of the neurones themselves or a partial function of their afferent inputs, by interrupting synaptic input activity via central administration of the L-type Ca(2+) channel blocker verapamil. In morphine-dependent rats, withdrawal-induced release of oxytocin from the posterior pituitary was suppressed by prior administration of intracerebroventricular (i.c.v.) verapamil (160 microg), as was release of oxytocin within the SON measured by microdialysis. During morphine withdrawal the increased electrical activity of SON neurones was also reduced both by i.c.v. verapamil and microdialysis application of verapamil or nifedipine into the SON. Oxytocin secretion evoked by electrical stimulation of the pituitary stalk was unaffected by i.c.v. verapamil suggesting a central site of action. To determine whether the inhibitory actions of verapamil were specific to morphine withdrawal, we also investigated the effects of verapamil on other oxytocin-secreting stimuli. I.C.V. verapamil given to morphine-naïve rats abolished pituitary oxytocin release in response to activation of brainstem or rostral excitatory inputs by cholecystokinin (20 microg kg(-1), i.v.) and 1.5 M saline (4 ml kg(-1), i.p.) respectively, whilst in lactating rats, i.c.v. verapamil reduced suckling-induced release of oxytocin within the SON. These results suggest that verapamil has a central site of action on stimulated oxytocin release (including an action within the SON) and that both pre and post-synaptic L-type Ca(2+) channels are required for the full expression of morphine withdrawal in SON oxytocin neurones.


Subject(s)
Calcium Channel Blockers/pharmacology , Morphine Dependence/physiopathology , Neurons/drug effects , Substance Withdrawal Syndrome/prevention & control , Verapamil/pharmacology , Animals , Animals, Suckling , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/physiology , Electric Stimulation , Female , Hypertonic Solutions/pharmacology , Injections, Intraventricular , Lactation , Membrane Potentials/drug effects , Microdialysis , Morphine/adverse effects , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Narcotics/adverse effects , Neurons/metabolism , Neurons/physiology , Oxytocin/drug effects , Oxytocin/metabolism , Pituitary Gland/drug effects , Pituitary Gland/physiology , Rats , Rats, Sprague-Dawley , Sincalide/analogs & derivatives , Sincalide/pharmacology , Substance Withdrawal Syndrome/physiopathology , Succinimides/pharmacology , Supraoptic Nucleus/cytology , Supraoptic Nucleus/drug effects , Supraoptic Nucleus/metabolism
7.
J Gen Virol ; 80 ( Pt 9): 2433-2436, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10501498

ABSTRACT

Following the establishment of a chronic varicella-zoster virus infection in the rat, behavioural allodynia and hyperalgesia were observed in the injected, but not the contralateral hind limb up to 33 days post-infection. This model may prove useful in investigating mechanisms involved in the establishment of post-herpetic neuralgia.


Subject(s)
Behavior, Animal , Herpes Zoster/psychology , Animals , Herpes Zoster/physiopathology , Hyperalgesia , Male , Pain/physiopathology , Rats , Rats, Wistar , Viral Proteins/analysis
8.
Neuroscience ; 90(1): 153-64, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10188942

ABSTRACT

Neuropathic pain is thought to arise from ectopic discharges at the site of injury within the peripheral nervous system, and is manifest as a general increase in the level of neuronal excitability within primary afferent fibres and their synaptic contacts within the spinal cord. Voltage-activated Na+ channel blockers such as lamotrigine have been shown to be clinically effective in the treatment of neuropathic pain. Na+ channels are structurally diverse comprising a principal a subunit (of which there are variable isoforms) and two auxiliary subunits termed beta1 and beta2. Both beta subunits affect the rates of channel activation and inactivation, and can modify alpha subunit density within the plasma membrane. In addition, these subunits may interact with extracellular matrix molecules to affect growth and myelination of axons. Using in situ hybridization histochemistry we have shown that the expression of the beta1 and beta2 subunits within the dorsal horn of the spinal cord of neuropathic rats is differentially regulated by a chronic constrictive injury to the sciatic nerve. At days 12-15 post-neuropathy, beta1 messenger RNA levels had increased, whereas beta2 messenger RNA levels had decreased significantly within laminae I, II on the ipsilateral side of the cord relative to the contralateral side. Within laminae III-IV beta2 messenger RNA levels showed a small but significant decrease on the ipsilateral side relative to the contralateral side, whilst expression of beta1 messenger RNA remained unchanged. Thus, differential regulation of the individual beta subunit types may (through their distinct influences on Na+ channel function) contribute to altered excitability of central neurons after neuropathic injury.


Subject(s)
Ganglia, Spinal/physiopathology , Gene Expression Regulation/drug effects , Hyperalgesia/physiopathology , Sodium Channels/biosynthesis , Spinal Cord/metabolism , Animals , Cold Temperature , Ganglia, Spinal/drug effects , Hyperalgesia/genetics , Image Processing, Computer-Assisted , In Situ Hybridization , Ion Channel Gating/drug effects , Ion Transport/drug effects , Male , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Wistar , Sodium Channels/chemistry , Sodium Channels/genetics , Spinal Cord/physiopathology , Tetrodotoxin/pharmacology , Vasoactive Intestinal Peptide/biosynthesis , Vasoactive Intestinal Peptide/genetics
9.
J Neurosci ; 18(23): 10180-8, 1998 Dec 01.
Article in English | MEDLINE | ID: mdl-9822771

ABSTRACT

Electrophysiological and behavioral studies point to a role of group I metabotropic glutamate receptors (mGluR1 and mGluR5) in mediating spinal nociceptive responses in rats. However, antagonists with a high degree of specificity for each of these sites are not yet available. We, therefore, examined the effects of antisense deletion of spinal mGluR1 expression in assays of behavioral analgesia and of electrophysiological responses of dorsal horn neurons. Rats treated with an mGluR1 antisense oligonucleotide reagent, delivered continuously to the intrathecal space of the lumbar spinal cord, developed marked analgesia as measured by an increase in the latency to tail-flick (55 degreesC) over a period of 4-7 d. This correlated with a selective reduction in mGluR1, but not mGluR5, immunoreactivity in the superficial dorsal horn compared with untreated control rats, in parallel with a significant reduction in the proportion of neurons activated by the mGluR group I agonist 3, 5-dihydroxyphenylglycine (DHPG), whereas the proportion of cells excited by the mGluR5 agonist, trans-azetidine-2,4-dicarboxylic acid (t-ADA) remained unaffected. In contrast, rats treated with mGluR1 sense or mismatch probes showed none of these changes compared with untreated, control rats. Furthermore, multireceptive dorsal horn neurons in mGluR1 antisense-treated rats were strongly excited by innocuous stimuli to their peripheral receptive fields, but showed severe reductions in their sustained excitatory responses to the selective C-fiber activator mustard oil and in responses to DHPG.


Subject(s)
Nociceptors/physiology , Receptors, Metabotropic Glutamate/genetics , Spinal Cord/cytology , Spinal Cord/physiology , Synaptic Transmission/physiology , Animals , Antisense Elements (Genetics) , Azetidinecarboxylic Acid/analogs & derivatives , Azetidinecarboxylic Acid/pharmacology , Behavior, Animal/physiology , Electrophysiology , Excitatory Amino Acid Agonists/pharmacology , Gene Deletion , Glycine/analogs & derivatives , Glycine/pharmacology , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mutagenesis/physiology , Rats , Rats, Wistar , Receptor, Metabotropic Glutamate 5 , Resorcinols/pharmacology , Synaptic Transmission/drug effects
10.
Neuroreport ; 8(7): 1549-54, 1997 May 06.
Article in English | MEDLINE | ID: mdl-9189890

ABSTRACT

Two voltage-activated Na+ channel blockers, lamotrigine and flunarizine were applied ionophoretically to extracellularly recorded dorsal horn neurones to assess effects on activation by noxious (mustard oil) and innocuous (brush) stimuli. Lamotrigine and flunarizine caused significantly greater reductions in mustard oil-evoked activity (> 50% in both cases) than in brush-evoked activity (13 +/- 7% and 29 +/- 6%; p < 6%; +/- 0.005 and p < 0.05 respectively) at equivalent ionophoretic currents. Similar results were observed when lamotrigine was administered i.v. Thus, the activation of dorsal horn neurones by nociceptive and non-nociceptive afferent inputs can be differentiated by the blockade of a lamotrigine/flunarizine-sensitive Na+ channel, at a spinal site.


Subject(s)
Analgesics/pharmacology , Evoked Potentials, Somatosensory/drug effects , Flunarizine/pharmacology , Ganglia, Spinal/drug effects , Sodium Channel Blockers , Triazines/pharmacology , Animals , Dose-Response Relationship, Drug , Glutamates/pharmacology , Lamotrigine , Male , Mustard Plant , Physical Stimulation , Plant Extracts/pharmacology , Plant Oils , Plants, Medicinal , Rats , Rats, Wistar
11.
Brain Res ; 777(1-2): 161-9, 1997 Nov 28.
Article in English | MEDLINE | ID: mdl-9449425

ABSTRACT

A combined study of behavioural and electrophysiological tests was carried out in order to assess the role of metabotropic glutamate receptors (mGluRs) in mediating sensory inputs to the spinal cord of the rat. In the behavioural study the responses of conscious animals, with or without carrageenan-induced inflammation, to noxious mechanical and thermal stimuli were observed both before and after the intrathecal administration of mGluR antagonists L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and (S)-4-carboxy-3-hydroxyphenylglycine (CHPG). It was found that the mGluR antagonist (S)-CHPG was capable of increasing both mechanical threshold and thermal latency in both groups of animals, and L-AP3 did so in those with inflammation induced in their hindpaw. Following this study, the responses of single lamina III-V dorsal horn neurons to an innocuous A beta fibre brush stimulus and a noxious C fibre (mustard oil) stimulus were extracellularly recorded and the effect of ionophoretically applied drugs was examined. Cyclothiazide (CTZ), a selective antagonist at mGluR1, markedly reduced the activity evoked by mustard oil, but not that elicited by brushing of the receptive field. Activity induced in dorsal horn neurons by ionophoresing various mGluR subgroup agonists was examined. CTZ successfully inhibited the activity evoked by group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG). In comparison to the neurons which responded to the ionophoresis of DHPG, less were activated by the selective mGluR5 agonist trans-azetidine dicarboxylic acid (t-ADA). Together these results indicate that group I mGlu receptors, in particular mGluR1, play a crucial role in mediating nociception, particularly following a sustained noxious input.


Subject(s)
Behavior, Animal/physiology , Nociceptors/physiology , Pain/physiopathology , Receptors, Metabotropic Glutamate/physiology , Spinal Cord/physiology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Antihypertensive Agents/pharmacology , Benzothiadiazines/pharmacology , Cycloleucine/analogs & derivatives , Cycloleucine/pharmacology , Electrophysiology , Excitatory Amino Acid Antagonists/pharmacology , Female , Glycine/analogs & derivatives , Glycine/pharmacology , Male , Mustard Plant , Neuroprotective Agents/pharmacology , Nociceptors/drug effects , Phenylacetates/pharmacology , Plant Extracts , Plant Oils , Plants, Medicinal , Rats , Rats, Inbred Strains , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Resorcinols/pharmacology , Spinal Cord/chemistry
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