Attenuation by valproate of c‐fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin

Cutrer, F. Michael; Limmroth, Volker; Ayata, Gamze; Moskowitz, Michael A.

doi:10.1111/j.1476-5381.1995.tb15124.x

Cited by 83 publications

(49 citation statements)

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“…Although valproate does not block mechanically induced cortical spreading depression in the cat (Kaube & Goadsby, 1994), it has been proposed that an increase in inhibitory GABAergic neurotransmission may suppress the pathophysiological events that underlie migraine aura (Cutrer et al, 1997). Valproate selectively reduces c-Foslike immunoreactivity within lamina I and II o of the spinal cord (Cutrer et al, 1995). Pre-treatment with bicuculline, but not phaclofen, reversed the eect of valproate and increased the number of c-Fos positive cells within lamina I and II o of the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

“…The action of valproate may be mediated through GABA A receptors , whereas baclofen is a GABA B British Journal of Pharmacology (2001) 134, 896 ± 904 ã 2001 Nature Publishing Group All rights reserved 0007 ± 1188/01 $15.00 www.nature.com/bjp *Author for correspondence at: Institute of Neurology, Queen Square, London WC1N 3BG; E-mail: peterg@ion.ucl.ac.uk receptor agonist capable of crossing the blood brain barrier, although not all these compounds have exclusively GABAergic action. Expression of the proto-oncogene c-fos as a marker of nociceptive neuronal activity within the trigeminal nucleus caudalis is reduced by valproate (Cutrer et al, 1995) and allopregnanolone, a neurosteroid progesterone metabolite which modulates GABA A receptor activity through an allosteric binding site .Aerent ®bres conduct nociceptive information to the trigeminal nucleus caudalis. GABA A and GABA B receptors are located at both peripheral and central sites.…”

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GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex

Storer

Akerman

Goadsby

2001

British J Pharmacology

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1 GABA (g-aminobutyric acid) receptors involved in craniovascular nociceptive pathways were characterised by in vivo microiontophoresis of GABA receptor agonists and antagonists onto neurones in the trigeminocervical complex of the cat. 2 Extracellular recordings were made from neurones in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus, which were subsequently stimulated with L-glutamate. 3 Cell ®ring evoked by microiontophoretic application of L-glutamate (n=30) was reversibly inhibited by GABA in every cell tested (n=19), the GABA A agonist muscimol (n=10) in all cells tested, or both where tested, but not by iontophoresis of either sodium or chloride ions at comparable ejection currents. Inhibited cells received wide dynamic range (WDR) or nociceptive speci®c input from cutaneous receptive ®elds on the face or forepaws. 4 The inhibition of trigeminal neurones by GABA or muscimol could be antagonized by the GABA A antagonist N-methylbicuculline, 1(S),9(R) in all but two cells tested (n=16), but not by the GABA B antagonist 2-hydroxysaclofen (n=11). 5 R(7)-baclofen, a GABA B agonist, inhibited the ®ring of three out of seven cells activated by Lglutamate. Where tested, this inhibition could be antagonized by 2-hydroxysaclofen. These baclofeninhibited cells were characterized as having low threshold mechanoreceptor/WDR input. 6 GABA thus appears to modulate nociceptive input to the trigeminocervical complex mainly through GABA A receptors. GABA A receptors may therefore provide a target for the development of new therapeutic agents for primary headache disorders. British Journal of Pharmacology (2001) 134, 896 ± 904 Keywords: GABA; trigeminal nucleus caudalis; migraine; microiontophoresis Abbreviations: Baclofen, R(+)-baclofen hydrochloride; 2OH-saclofen, 2-hydroxysaclofen; GAD, glutamic acid dehydrogenase; LTM, low threshold mechanical; N-methylbicuculline, (7)-bicuculline metho-chloride/-bromide, 1(S),(9R); NS, nociceptive speci®c; PPE, plasma protein extravasation; SSS, superior sagittal sinus; TNC, trigeminal nucleus caudalis; WDR, wide dynamic range IntroductionThe pain in primary headache syndromes, such as migraine and cluster headache, is referred to the ophthalmic (®rst) division of the trigeminal nerve from pain-producing intracranial structures, such as the dura mater and large vessels, through the trigeminocervical complex (Goadsby, 2001). Modulation of trigeminal transmission in order to alleviate acute migraine requires an understanding of the pharmacology of the synapse onto second order trigeminal neurones. In recent years the pharmacology of this synapse has begun to be studied with most attention on serotonergic and glutamatergic transmission (Goadsby, 1999a). g-Aminobutyric acid (GABA) is well known as an inhibitory amino acid neurotransmitter in the central nervous system (CNS) (Roberts, 1976) and may modulate nociceptive response in spinal cord (Roberts et al., 1986). Its role in trigeminovascular nociceptive transmission within t...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex

Storer

Akerman

Goadsby

2001

British J Pharmacology

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“…Studies using microiontophoresis determined that -receptor agonists inhibit neurons in the TNC post-synaptic to trigeminal afferents [45]. Valproic acid, an inhibitor of γ aminobutyric acid (GABA) aminotransferase, when applied to the rat in the trigeminocervical nociceptive models, reduced the expression of c-fos-positive cells in the TNC [46] after trigeminal stimulation. Electrophysiologic studies, combined with microiontophoresis, also suggested that GABA receptors modulate trigeminovascular nociceptive transmission in the trigeminocervical complex [47].…”

Section: Laboratory Studiesmentioning

confidence: 99%

Convergence of cervical and trigeminal sensory afferents

Piovesan¹,

Kowacs²,

Oshinsky³

2003

Current Science Inc

141

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Cranial nociceptive perception shows a distinct topographic distribution, with the trigeminal nerve receiving sensory information from the anterior portions of the head, the greater occipital nerve, and branches of the upper cervical roots in the posterior regions. However, this distribution is not respected during headache attacks, even if the etiology of the headache is specific for only one nerve. Nociceptive information from the trigeminal and cervical territories activates the neurons in the trigeminal nucleus caudalis that extend to the C2 spinal segment and lateral cervical nucleus in the dorsolateral cervical area. These neurons are classified as multimodal because they receive sensory information from more than one afferent type. Clinically, trigeminal activation produces symptoms in the trigeminal and cervical territory and cervical activation produces symptoms in the cervical and trigeminal territory. The overlap between the trigeminal nerve and cervical is known as a convergence mechanism. For some time, convergence mechanisms were thought to be secondary to clinical observations. However, animal studies and clinical evidence have expanded our knowledge of convergence mechanisms. In this paper, the role of convergence mechanisms in nociceptive physiology, physiopathology of the headaches, clinical diagnosis, and therapeutic conduct are reviewed.

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“…It is generally accepted GABA B receptors are mainly located on A d and C primary afferent terminals and are involved in the presynaptic inhibition of these endings and produce analgesia (Price et al 1987;Castro-lopes et al 1995). Baclofen may prevent neurogenic pain by its synergistic presynaptic and postsynaptic inhibition in sensory pathways and prevents neuronal discharges (Losada & Acosta 1992;Hering-Hanit 1999), inhibits stimulus in the trigeminal nucleus (Fromm et al 1992), inhibits the release of substance P (Saito et al 1975) and decreases both c-fos expression and neurogenic inflammation within the meninges (Cutrer et al 1995). This may support our present data which show that the antinociceptive response of muscimol or baclofen did not differ between intact or nerve-ligated mice.…”

Section: Discussionmentioning

confidence: 99%

GABA Mechanisms and Antinociception in Mice with Ligated Sciatic Nerve

Zarrindast

Mahmoudi

2001

Pharmacology & Toxicology

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In the present study, the effects of GABA (g-aminobutyric acid) receptor agonists and antagonists on hyperalgesia induced by sciatic nerve ligation was investigated in mice. The response to morphine or GABA receptor agonists was examined 14 days after unilateral nerve ligation by hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), muscimol (0.5, 1 and 2 mg/kg) or baclofen (1, 2.5 and 5 mg/kg) induced a dose-related antinociception in both intact and ligated mice. The response of morphine but not that of muscimol or baclofen, in nerve-ligated mice was significantly less than that induced in the intact animals. The responses induced by muscimol or baclofen in nerveligated animals, were reduced by bicuculline or CGP35348 [P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid], respectively. However, morphine in combination with muscimol (2 mg/kg) tends to induce higher response; the combination of the GABA receptor agonists with morphine did not show potentiation, but additive effect. The opioid receptor antagonist naloxone reduced the response induced by muscimol in nerve-ligated animals. It was concluded that although ligation of the sciatic nerve clearly reduced the analgesic effect of morphine and not that of the GABA agonists, the results nevertheless indicated that morphine and the GABA A agonist shared the same mechanism of action.g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). GABA can interact with two, possibly three subtypes of GABA receptor, namely GABA A , GABA B and GABA C (Malcangio & Bowery 1996). The GABAmimetic agents may have a broad spectrum of pharmacological actions including analgesia (Enna 1983).GABA may influence opioid-induced antinociception (Kalyuzhny & Wessendorf 1998;Hara et al. 1999). The overlapping distribution of endogenous opioid and GABA neurotransmitter and of their receptors in the CNS has led to a large number of studies aimed at clarifying the functional relationship between opioid and GABA systems (Suh et al. 1995;Rady & Fujimoto 1996).Neuropathic pain arising from peripheral nerve injury can result in increased sensitivity to both noxious (hyperalgesia) and non-noxious stimuli (allodynia). The pain is accompanied by a number of neuroplastic alterations at the level of the spinal cord including up-regulation of neurotransmitters such as dynorphin and down-regulation of GABA (Stiller et al. 1996;Cui et al. 1997;Nichols et al. 1997). The lack of efficacy of opioids against neuropathic pain, produced by diseases or damage to the nervous system, not only reduces their effectiveness but also complicates the management of patients with persistent pain (Inturrisi 1990; Foley 1991).The well-established animal model of mononeuropathy produced by constriction injury of a sciatic nerve, has been extensively employed in the study of neuropathic pain mechanisms (Mao et al. 1995;Ossipov et al. 1995). In the present study, the antinociceptive effects of GABA receptor agents wi...

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Attenuation by valproate of c‐fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin

Cited by 83 publications

References 36 publications

GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex

GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex

Convergence of cervical and trigeminal sensory afferents

GABA Mechanisms and Antinociception in Mice with Ligated Sciatic Nerve

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