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Peter J Goadsby - One of the best experts on this subject based on the ideXlab platform.

  • calcitonin gene related peptide cgrp modulates nociceptive trigeminovascular transmission in the cat
    British Journal of Pharmacology, 2004
    Co-Authors: R J Storer, Simon Akerman, Peter J Goadsby
    Abstract:

    Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists α-CGRP-(8–37) and BIBN4096BS. Cats were anaesthetised with α-chloralose, and using halothane during surgical preparation. A craniotomy and C1/C2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for Microiontophoresis of test substances. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25–30 Hz by Microiontophoresis of L-glutamate (n=43 cells). Microiontophoresis of α-CGRP excited seven of 17 tested neurons. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by L-glutamate, demonstrating a non-presynaptic site of action for CGRP. α-CGRP-(8–37) inhibited a similar proportion of units (five of nine cells). Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED50 31 μg kg–1). The maximal effect observed within 30 min of administration. The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache. Keywords: Headache, migraine, cluster headache, CGRP antagonist, trigeminocervical complex Introduction The neurobiology of migraine essentially involves three components (Goadsby et al., 2002): first, the inherited migrainous diathesis, currently best characterized in familial hemiplegic migraine by mis-sense mutations in channel genes (Ophoff et al., 1996; De Fusco et al., 2003); secondly, migraine involves activation of brainstem regions (Weiller et al., 1995; Bahra et al., 2001; Matharu et al., 2003) that uniquely mark the condition when compared to other forms of primary headache, such as cluster headache (May et al., 1998); thirdly, the pain component of migraine seems to involve activation (Goadsby et al., 1990), or at least the perception of activation, of the trigeminal innervation of pain-producing intracranial components (Wolff, 1948). The trigeminal innervation of the cranial circulation contains a number of neuropeptides, including calcitonin gene-related peptide (CGRP) (Edvinsson et al., 1987). During acute migraine and cluster headache, CGRP levels are elevated in both adults and adolescents (Edvinsson & Goadsby, 1998), so that the effect of CGRP antagonists on models of trigeminovascular nociception may aid in understanding the potential role of such compounds in these disorders. Stimulation of the trigeminal ganglion in cat and humans results in elevations in CGRP and substance P levels in the cranial circulation (Goadsby et al., 1988). However, during acute attacks of migraine (Goadsby et al., 1990; Gallai et al., 1995) and cluster headache (Goadsby & Edvinsson, 1994a; Fanciullacci et al., 1995) CGRP is elevated but substance P is not. Triptans, serotonin (5-HT1B/1D) receptor agonists (Goadsby, 2000), which are effective in the treatment of acute migraine (Ferrari et al., 2001) and cluster headache (Ekbom & The Sumatriptan Cluster Headache Study Group, 1991), inhibit release of CGRP into the cranial circulation of experimental animals when it is evoked by trigeminal ganglion activation (Goadsby & Edvinsson, 1993; 1994b). Moreover, successful treatment of acute migraine (Goadsby & Edvinsson, 1993) or cluster headache (Goadsby & Edvinsson, 1994a; Fanciullacci et al., 1995) with sumatriptan normalises cranial CGRP levels. Stimulation of the superior sagittal sinus (SSS) in humans produces pain that is substantially referred to the first (ophthalmic) division of the trigeminal nerve (Feindel et al., 1960). During stimulation of the superior sagittal sinus (SSS), neurons can be studied using population-based anatomical techniques, such as measurement of Fos with immunohistochemistry (Kaube et al., 1993b), or metabolic activity with 2-deoxyglucose (Goadsby & Zagami, 1991), or single neurons can be more closely tracked using electrophysiological techniques (Hoskin et al., 1996; Cumberbatch et al., 1997). Electrophysiological methods incorporating Microiontophoresis facilitate characterization of the pharmacology of neurons of interest by repeated local application of appropriate agonist and antagonist combinations (Bloom, 1974). It has been shown that neurons in the trigeminocervical complex of the cat or rat are inhibited by administration of triptans intravenously or by Microiontophoresis, or both (Goadsby, 2000). In this study, we determined whether the peripheral release of CGRP in the cranial circulation during acute migraine was mirrored in the trigeminocervical complex. The development of a potent specific CGRP receptor antagonist in the form of BIBN4096BS facilitates addressing this issue (Doods et al., 2000). By combining intravenous and microiontophoretic application of CGRP receptor antagonists, we determine here that there is a non-presynaptic CGRP receptor in the trigeminal nucleus that is a potential therapeutic target in migraine and cluster headache.

R J Storer - One of the best experts on this subject based on the ideXlab platform.

  • calcitonin gene related peptide cgrp modulates nociceptive trigeminovascular transmission in the cat
    British Journal of Pharmacology, 2004
    Co-Authors: R J Storer, Simon Akerman, Peter J Goadsby
    Abstract:

    Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists α-CGRP-(8–37) and BIBN4096BS. Cats were anaesthetised with α-chloralose, and using halothane during surgical preparation. A craniotomy and C1/C2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for Microiontophoresis of test substances. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25–30 Hz by Microiontophoresis of L-glutamate (n=43 cells). Microiontophoresis of α-CGRP excited seven of 17 tested neurons. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by L-glutamate, demonstrating a non-presynaptic site of action for CGRP. α-CGRP-(8–37) inhibited a similar proportion of units (five of nine cells). Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED50 31 μg kg–1). The maximal effect observed within 30 min of administration. The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache. Keywords: Headache, migraine, cluster headache, CGRP antagonist, trigeminocervical complex Introduction The neurobiology of migraine essentially involves three components (Goadsby et al., 2002): first, the inherited migrainous diathesis, currently best characterized in familial hemiplegic migraine by mis-sense mutations in channel genes (Ophoff et al., 1996; De Fusco et al., 2003); secondly, migraine involves activation of brainstem regions (Weiller et al., 1995; Bahra et al., 2001; Matharu et al., 2003) that uniquely mark the condition when compared to other forms of primary headache, such as cluster headache (May et al., 1998); thirdly, the pain component of migraine seems to involve activation (Goadsby et al., 1990), or at least the perception of activation, of the trigeminal innervation of pain-producing intracranial components (Wolff, 1948). The trigeminal innervation of the cranial circulation contains a number of neuropeptides, including calcitonin gene-related peptide (CGRP) (Edvinsson et al., 1987). During acute migraine and cluster headache, CGRP levels are elevated in both adults and adolescents (Edvinsson & Goadsby, 1998), so that the effect of CGRP antagonists on models of trigeminovascular nociception may aid in understanding the potential role of such compounds in these disorders. Stimulation of the trigeminal ganglion in cat and humans results in elevations in CGRP and substance P levels in the cranial circulation (Goadsby et al., 1988). However, during acute attacks of migraine (Goadsby et al., 1990; Gallai et al., 1995) and cluster headache (Goadsby & Edvinsson, 1994a; Fanciullacci et al., 1995) CGRP is elevated but substance P is not. Triptans, serotonin (5-HT1B/1D) receptor agonists (Goadsby, 2000), which are effective in the treatment of acute migraine (Ferrari et al., 2001) and cluster headache (Ekbom & The Sumatriptan Cluster Headache Study Group, 1991), inhibit release of CGRP into the cranial circulation of experimental animals when it is evoked by trigeminal ganglion activation (Goadsby & Edvinsson, 1993; 1994b). Moreover, successful treatment of acute migraine (Goadsby & Edvinsson, 1993) or cluster headache (Goadsby & Edvinsson, 1994a; Fanciullacci et al., 1995) with sumatriptan normalises cranial CGRP levels. Stimulation of the superior sagittal sinus (SSS) in humans produces pain that is substantially referred to the first (ophthalmic) division of the trigeminal nerve (Feindel et al., 1960). During stimulation of the superior sagittal sinus (SSS), neurons can be studied using population-based anatomical techniques, such as measurement of Fos with immunohistochemistry (Kaube et al., 1993b), or metabolic activity with 2-deoxyglucose (Goadsby & Zagami, 1991), or single neurons can be more closely tracked using electrophysiological techniques (Hoskin et al., 1996; Cumberbatch et al., 1997). Electrophysiological methods incorporating Microiontophoresis facilitate characterization of the pharmacology of neurons of interest by repeated local application of appropriate agonist and antagonist combinations (Bloom, 1974). It has been shown that neurons in the trigeminocervical complex of the cat or rat are inhibited by administration of triptans intravenously or by Microiontophoresis, or both (Goadsby, 2000). In this study, we determined whether the peripheral release of CGRP in the cranial circulation during acute migraine was mirrored in the trigeminocervical complex. The development of a potent specific CGRP receptor antagonist in the form of BIBN4096BS facilitates addressing this issue (Doods et al., 2000). By combining intravenous and microiontophoretic application of CGRP receptor antagonists, we determine here that there is a non-presynaptic CGRP receptor in the trigeminal nucleus that is a potential therapeutic target in migraine and cluster headache.

Weixing Shi - One of the best experts on this subject based on the ideXlab platform.

  • effects of scopolamine on dopamine neurons in the substantia nigra role of the pedunculopontine tegmental nucleus
    Synapse, 2009
    Co-Authors: Giuseppe Di Giovanni, Weixing Shi
    Abstract:

    Previous neurochemical and behavioral studies suggest that muscarinic receptor antagonism has an excitatory effect on the nigrostriatal dopamine (DA) system. Using in vivo extracellular single unit recording, this study examined whether blockade of the muscarinic receptor by scopolamine alters the firing properties of DA neurons in the substantia nigra (SN). Scopolamine was administered either systemically or locally to DA neurons using Microiontophoresis. Surprisingly, scopolamine did not cause any significant change in either the firing rate or pattern of the spontaneously active DA neurons. However, systemic injection of scopolamine significantly increased the number of active DA neurons in the SN. Local infusion of scopolamine into the pedunculopontine tegmental nucleus (PPT) mimicked the effect induced by systemically administered scopolamine, significantly increasing the number of active DA neurons without altering the firing rate and pattern. These results suggest that the reported increase in striatal DA release induced by scopolamine is in part mediated by activation of silent nigral DA neurons. The experiments with PPT local infusion further suggest that part of the effect of scopolamine may be due to its blockade of the inhibitory muscarinic autoreceptors on PPT cholinergic cells. The latter effect may lead to activation of quiescent DA neurons by increasing acetylcholine (ACh) release in the SN or in other brain areas providing inputs to DA neurons. Further understanding of the mechanism of action of scopolamine may help us further understand the role of ACh in both the pathophysiology and treatment of DA-related disorders including schizophrenia and Parkinson's disease.

Goadsby P J - One of the best experts on this subject based on the ideXlab platform.

  • Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat
    2004
    Co-Authors: Storer, Robin James, Akerman Simon, Goadsby P J
    Abstract:

    1. Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists α-CGRP-(8–37) and BIBN4096BS. 2. Cats were anaesthetised with α-chloralose, and using halothane during surgical preparation. A craniotomy and C(1)/C(2) laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for Microiontophoresis of test substances. 3. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25–30 Hz by Microiontophoresis of L-glutamate (n=43 cells). 4. Microiontophoresis of α-CGRP excited seven of 17 tested neurons. 5. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by L-glutamate, demonstrating a non-presynaptic site of action for CGRP. α-CGRP-(8–37) inhibited a similar proportion of units (five of nine cells). 6. Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED(50) 31 μg kg(–1)). The maximal effect observed within 30 min of administration. 7. The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache

  • Characterization of opioid receptors that modulate nociceptive neurotransmission in the trigeminocervical complex
    2003
    Co-Authors: Storer R J, Akerman S, Goadsby P J
    Abstract:

    1. Opioid agonists have been used for many years to treat all forms of headache, including migraine. We sought to characterize opioid receptors involved in craniovascular nociceptive pathways by in vivo Microiontophoresis of μ-receptor agonists and antagonists onto neurons in the trigeminocervical complex of the cat. 2. Cats were anaesthetized with α-chloralose 60 mg kg(−1), i.p. and 20 mg kg(−1), i.v. supplements after induction and surgical preparation using halothane. Units were identified in the trigeminocervical complex responding to supramaximal electrical stimulation of the superior sagittal sinus, and extracellular recordings of activity made. 3. Seven- or nine-barrelled glass micropipettes incorporating tungsten recording electrodes in their centre barrels were used for Microiontophoresis of test substances onto cell bodies. 4. Superior sagittal sinus (SSS)-linked cells whose firing was evoked by microiontophoretic application of L-glutamate (n=8 cells) were reversibly inhibited by Microiontophoresis of H(2)N-Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) (n=12), a selective μ-receptor agonist, in a dose dependent manner, but not by control ejection of sodium or chloride ions from a barrel containing saline. 5. The inhibition by DAMGO of SSS-linked neurons activated with L-glutamate could be antagonized by Microiontophoresis of selective μ-receptor antagonists D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or both, in all cells tested (n=4 and 6, respectively). 6. Local iontophoresis of DAMGO during stimulation of the superior sagittal sinus resulted in a reduction in SSS-evoked activity. This effect was substantially reversed 10 min after cessation of iontophoresis. The effect of DAMGO was markedly inhibited by co-iontophoresis of CTAP. 7. Thus, we found that μ-receptors modulate nociceptive input to the trigeminocervical complex. Characterizing the sub-types of opioid receptors that influence trigeminovascular nociceptive transmission is an important component to understanding the pharmacology of this synapse, which is pivotal in primary neurovascular headache

  • GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex
    2001
    Co-Authors: Storer, Robin James, Akerman Simon, Goadsby P J
    Abstract:

    1. GABA (γ-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 firing 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 specific input from cutaneous receptive fields 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(−)-baclofen, a GABA(B) agonist, inhibited the firing of three out of seven cells activated by L-glutamate. Where tested, this inhibition could be antagonized by 2-hydroxysaclofen. These baclofen-inhibited 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

Simon Akerman - One of the best experts on this subject based on the ideXlab platform.

  • calcitonin gene related peptide cgrp modulates nociceptive trigeminovascular transmission in the cat
    British Journal of Pharmacology, 2004
    Co-Authors: R J Storer, Simon Akerman, Peter J Goadsby
    Abstract:

    Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists α-CGRP-(8–37) and BIBN4096BS. Cats were anaesthetised with α-chloralose, and using halothane during surgical preparation. A craniotomy and C1/C2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for Microiontophoresis of test substances. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25–30 Hz by Microiontophoresis of L-glutamate (n=43 cells). Microiontophoresis of α-CGRP excited seven of 17 tested neurons. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by L-glutamate, demonstrating a non-presynaptic site of action for CGRP. α-CGRP-(8–37) inhibited a similar proportion of units (five of nine cells). Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED50 31 μg kg–1). The maximal effect observed within 30 min of administration. The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache. Keywords: Headache, migraine, cluster headache, CGRP antagonist, trigeminocervical complex Introduction The neurobiology of migraine essentially involves three components (Goadsby et al., 2002): first, the inherited migrainous diathesis, currently best characterized in familial hemiplegic migraine by mis-sense mutations in channel genes (Ophoff et al., 1996; De Fusco et al., 2003); secondly, migraine involves activation of brainstem regions (Weiller et al., 1995; Bahra et al., 2001; Matharu et al., 2003) that uniquely mark the condition when compared to other forms of primary headache, such as cluster headache (May et al., 1998); thirdly, the pain component of migraine seems to involve activation (Goadsby et al., 1990), or at least the perception of activation, of the trigeminal innervation of pain-producing intracranial components (Wolff, 1948). The trigeminal innervation of the cranial circulation contains a number of neuropeptides, including calcitonin gene-related peptide (CGRP) (Edvinsson et al., 1987). During acute migraine and cluster headache, CGRP levels are elevated in both adults and adolescents (Edvinsson & Goadsby, 1998), so that the effect of CGRP antagonists on models of trigeminovascular nociception may aid in understanding the potential role of such compounds in these disorders. Stimulation of the trigeminal ganglion in cat and humans results in elevations in CGRP and substance P levels in the cranial circulation (Goadsby et al., 1988). However, during acute attacks of migraine (Goadsby et al., 1990; Gallai et al., 1995) and cluster headache (Goadsby & Edvinsson, 1994a; Fanciullacci et al., 1995) CGRP is elevated but substance P is not. Triptans, serotonin (5-HT1B/1D) receptor agonists (Goadsby, 2000), which are effective in the treatment of acute migraine (Ferrari et al., 2001) and cluster headache (Ekbom & The Sumatriptan Cluster Headache Study Group, 1991), inhibit release of CGRP into the cranial circulation of experimental animals when it is evoked by trigeminal ganglion activation (Goadsby & Edvinsson, 1993; 1994b). Moreover, successful treatment of acute migraine (Goadsby & Edvinsson, 1993) or cluster headache (Goadsby & Edvinsson, 1994a; Fanciullacci et al., 1995) with sumatriptan normalises cranial CGRP levels. Stimulation of the superior sagittal sinus (SSS) in humans produces pain that is substantially referred to the first (ophthalmic) division of the trigeminal nerve (Feindel et al., 1960). During stimulation of the superior sagittal sinus (SSS), neurons can be studied using population-based anatomical techniques, such as measurement of Fos with immunohistochemistry (Kaube et al., 1993b), or metabolic activity with 2-deoxyglucose (Goadsby & Zagami, 1991), or single neurons can be more closely tracked using electrophysiological techniques (Hoskin et al., 1996; Cumberbatch et al., 1997). Electrophysiological methods incorporating Microiontophoresis facilitate characterization of the pharmacology of neurons of interest by repeated local application of appropriate agonist and antagonist combinations (Bloom, 1974). It has been shown that neurons in the trigeminocervical complex of the cat or rat are inhibited by administration of triptans intravenously or by Microiontophoresis, or both (Goadsby, 2000). In this study, we determined whether the peripheral release of CGRP in the cranial circulation during acute migraine was mirrored in the trigeminocervical complex. The development of a potent specific CGRP receptor antagonist in the form of BIBN4096BS facilitates addressing this issue (Doods et al., 2000). By combining intravenous and microiontophoretic application of CGRP receptor antagonists, we determine here that there is a non-presynaptic CGRP receptor in the trigeminal nucleus that is a potential therapeutic target in migraine and cluster headache.