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Sumatriptan inhibits synaptic transmission in the rat midbrain periaqueductal grey.

Jeong HJ, Chenu D, Johnson EE, Connor M, Vaughan CW - Mol Pain (2008)

Bottom Line: Sumatriptan also inhibited evoked IPSCs with an IC50 of 261 nM, and reduced the rate, but not the amplitude of spontaneous miniature IPSCs.The sumatriptan (1 microM) induced inhibition of evoked IPSCs was abolished by NAS181 (10 microM) and BRL15572 (10 microM), together, but not separately. 5-HT (10 microM) and sumatriptan (3 microM) also reduced the amplitude of non-NMDA mediated evoked excitatory postsynaptic currents (EPSCs) in all PAG neurons tested.These results indicate that sumatriptan inhibits GABAergic and glutamatergic synaptic transmission within the PAG via a 5-HT1B/D receptor mediated reduction in the probability of neurotransmitter release from nerve terminals.

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Affiliation: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, NSW 2065, Australia. jeong@med.usyd.edu.au

ABSTRACT

Background: There is evidence to suggest that the midbrain periaqueductal grey (PAG) has a role in migraine and the actions of the anti-migraine drug sumatriptan. In the present study we examined the serotonergic modulation of GABAergic and glutamatergic synaptic transmission in rat midbrain PAG slices in vitro.

Results: Serotonin (5-hydroxytriptamine, 5-HT, IC50 = 142 nM) and the selective serotonin reuptake inhibitor fluoxetine (30 microM) produced a reduction in the amplitude of GABAA-mediated evoked inhibitory postsynaptic currents (IPSCs) in all PAG neurons which was associated with an increase in the paired-pulse ratio of evoked IPSCs. Real time PCR revealed that 5-HT1A, 5-HT1B, 5-HT1D and 5-HT1F receptor mRNA was present in the PAG. The 5-HT1A, 5-HT1B and 5-HT1D receptor agonists 8-OH-DPAT (3 microM), CP93129 (3 microM) and L694247 (3 microM), but not the 5-HT1F receptor agonist LY344864 (1 - 3 microM) inhibited evoked IPSCs. The 5-HT (1 microM) induced inhibition of evoked IPSCs was abolished by the 5-HT1B antagonist NAS181 (10 microM), but not by the 5-HT1A and 5-HT1D antagonists WAY100135 (3 microM) and BRL15572 (10 microM). Sumatriptan also inhibited evoked IPSCs with an IC50 of 261 nM, and reduced the rate, but not the amplitude of spontaneous miniature IPSCs. The sumatriptan (1 microM) induced inhibition of evoked IPSCs was abolished by NAS181 (10 microM) and BRL15572 (10 microM), together, but not separately. 5-HT (10 microM) and sumatriptan (3 microM) also reduced the amplitude of non-NMDA mediated evoked excitatory postsynaptic currents (EPSCs) in all PAG neurons tested.

Conclusion: These results indicate that sumatriptan inhibits GABAergic and glutamatergic synaptic transmission within the PAG via a 5-HT1B/D receptor mediated reduction in the probability of neurotransmitter release from nerve terminals. These actions overlap those of other analgesics, such as opioids, and provide a mechanism by which centrally acting 5-HT1B and 5-HT1D ligands might lead to novel anti-migraine pharmacotherapies.

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Sumatriptan inhibits evoked IPSCs in PAG neurons. (A) Time course of evoked IPSC amplitude (eIPSC Ampl) during application of sumatriptan (3 μM). (B) Averaged evoked IPSCs before (control), during application of sumatriptan (3 μM) and following washout (wash). (C) Averaged evoked IPSCs in response to identical paired stimuli (IPSC1-2 interval = 70 ms) for the traces in B, with IPSC1 normalized to demonstrate relative facilitation of IPSC2 during superfusion of sumatriptan (3 μM). (D) Concentration-response curve of the reduction in evoked IPSC amplitude produced by sumatriptan, expressed as a percentage of the pre-sumatriptan level, with a logistic function fitted to determine the IC50. (E) Bar chart showing the evoked IPSC amplitude in the presence of sumatriptan (1 μM), expressed as a percentage of the pre- sumatriptan level, in neurons which received no prior treatment (control) and those which were pre-incubated in BRL15572 (10 μM) and/or NAS181 (10 μM). In (E) *, ** denote p < 0.05, 0.01. Traces in (A – C) are from the same neuron.
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Figure 5: Sumatriptan inhibits evoked IPSCs in PAG neurons. (A) Time course of evoked IPSC amplitude (eIPSC Ampl) during application of sumatriptan (3 μM). (B) Averaged evoked IPSCs before (control), during application of sumatriptan (3 μM) and following washout (wash). (C) Averaged evoked IPSCs in response to identical paired stimuli (IPSC1-2 interval = 70 ms) for the traces in B, with IPSC1 normalized to demonstrate relative facilitation of IPSC2 during superfusion of sumatriptan (3 μM). (D) Concentration-response curve of the reduction in evoked IPSC amplitude produced by sumatriptan, expressed as a percentage of the pre-sumatriptan level, with a logistic function fitted to determine the IC50. (E) Bar chart showing the evoked IPSC amplitude in the presence of sumatriptan (1 μM), expressed as a percentage of the pre- sumatriptan level, in neurons which received no prior treatment (control) and those which were pre-incubated in BRL15572 (10 μM) and/or NAS181 (10 μM). In (E) *, ** denote p < 0.05, 0.01. Traces in (A – C) are from the same neuron.

Mentions: When sumatriptan (1 – 10 μM) was superfused onto midbrain slices, it produced a reduction in the amplitude of evoked IPSCs in all PAG neurons tested (Figure 5a, b, p < 0.001, n = 16). The inhibition of evoked IPSCs produced by sumatriptan was concentration dependent, with an IC50 of 261 nM (90% confidence interval = 42 – 1,610 nM) and a Hill slope of 0.64 ± 0.22 (Figure 5d). The sumatriptan induced inhibition only partially reversed after a lengthy washout period at concentrations of 1 μM and above (Figure 5a), as observed by others [13,31]. Sumatriptan (1 – 10 μM) also increased the ratio of evoked IPSC2/IPSC1 from 1.26 ± 0.1 to 1.37 ± 0.1 (Figure 5c, p = 0.02, n = 16). Sumatriptan had no effect on membrane current, or conductance of neurons at -65 mV.


Sumatriptan inhibits synaptic transmission in the rat midbrain periaqueductal grey.

Jeong HJ, Chenu D, Johnson EE, Connor M, Vaughan CW - Mol Pain (2008)

Sumatriptan inhibits evoked IPSCs in PAG neurons. (A) Time course of evoked IPSC amplitude (eIPSC Ampl) during application of sumatriptan (3 μM). (B) Averaged evoked IPSCs before (control), during application of sumatriptan (3 μM) and following washout (wash). (C) Averaged evoked IPSCs in response to identical paired stimuli (IPSC1-2 interval = 70 ms) for the traces in B, with IPSC1 normalized to demonstrate relative facilitation of IPSC2 during superfusion of sumatriptan (3 μM). (D) Concentration-response curve of the reduction in evoked IPSC amplitude produced by sumatriptan, expressed as a percentage of the pre-sumatriptan level, with a logistic function fitted to determine the IC50. (E) Bar chart showing the evoked IPSC amplitude in the presence of sumatriptan (1 μM), expressed as a percentage of the pre- sumatriptan level, in neurons which received no prior treatment (control) and those which were pre-incubated in BRL15572 (10 μM) and/or NAS181 (10 μM). In (E) *, ** denote p < 0.05, 0.01. Traces in (A – C) are from the same neuron.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2588575&req=5

Figure 5: Sumatriptan inhibits evoked IPSCs in PAG neurons. (A) Time course of evoked IPSC amplitude (eIPSC Ampl) during application of sumatriptan (3 μM). (B) Averaged evoked IPSCs before (control), during application of sumatriptan (3 μM) and following washout (wash). (C) Averaged evoked IPSCs in response to identical paired stimuli (IPSC1-2 interval = 70 ms) for the traces in B, with IPSC1 normalized to demonstrate relative facilitation of IPSC2 during superfusion of sumatriptan (3 μM). (D) Concentration-response curve of the reduction in evoked IPSC amplitude produced by sumatriptan, expressed as a percentage of the pre-sumatriptan level, with a logistic function fitted to determine the IC50. (E) Bar chart showing the evoked IPSC amplitude in the presence of sumatriptan (1 μM), expressed as a percentage of the pre- sumatriptan level, in neurons which received no prior treatment (control) and those which were pre-incubated in BRL15572 (10 μM) and/or NAS181 (10 μM). In (E) *, ** denote p < 0.05, 0.01. Traces in (A – C) are from the same neuron.
Mentions: When sumatriptan (1 – 10 μM) was superfused onto midbrain slices, it produced a reduction in the amplitude of evoked IPSCs in all PAG neurons tested (Figure 5a, b, p < 0.001, n = 16). The inhibition of evoked IPSCs produced by sumatriptan was concentration dependent, with an IC50 of 261 nM (90% confidence interval = 42 – 1,610 nM) and a Hill slope of 0.64 ± 0.22 (Figure 5d). The sumatriptan induced inhibition only partially reversed after a lengthy washout period at concentrations of 1 μM and above (Figure 5a), as observed by others [13,31]. Sumatriptan (1 – 10 μM) also increased the ratio of evoked IPSC2/IPSC1 from 1.26 ± 0.1 to 1.37 ± 0.1 (Figure 5c, p = 0.02, n = 16). Sumatriptan had no effect on membrane current, or conductance of neurons at -65 mV.

Bottom Line: Sumatriptan also inhibited evoked IPSCs with an IC50 of 261 nM, and reduced the rate, but not the amplitude of spontaneous miniature IPSCs.The sumatriptan (1 microM) induced inhibition of evoked IPSCs was abolished by NAS181 (10 microM) and BRL15572 (10 microM), together, but not separately. 5-HT (10 microM) and sumatriptan (3 microM) also reduced the amplitude of non-NMDA mediated evoked excitatory postsynaptic currents (EPSCs) in all PAG neurons tested.These results indicate that sumatriptan inhibits GABAergic and glutamatergic synaptic transmission within the PAG via a 5-HT1B/D receptor mediated reduction in the probability of neurotransmitter release from nerve terminals.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, NSW 2065, Australia. jeong@med.usyd.edu.au

ABSTRACT

Background: There is evidence to suggest that the midbrain periaqueductal grey (PAG) has a role in migraine and the actions of the anti-migraine drug sumatriptan. In the present study we examined the serotonergic modulation of GABAergic and glutamatergic synaptic transmission in rat midbrain PAG slices in vitro.

Results: Serotonin (5-hydroxytriptamine, 5-HT, IC50 = 142 nM) and the selective serotonin reuptake inhibitor fluoxetine (30 microM) produced a reduction in the amplitude of GABAA-mediated evoked inhibitory postsynaptic currents (IPSCs) in all PAG neurons which was associated with an increase in the paired-pulse ratio of evoked IPSCs. Real time PCR revealed that 5-HT1A, 5-HT1B, 5-HT1D and 5-HT1F receptor mRNA was present in the PAG. The 5-HT1A, 5-HT1B and 5-HT1D receptor agonists 8-OH-DPAT (3 microM), CP93129 (3 microM) and L694247 (3 microM), but not the 5-HT1F receptor agonist LY344864 (1 - 3 microM) inhibited evoked IPSCs. The 5-HT (1 microM) induced inhibition of evoked IPSCs was abolished by the 5-HT1B antagonist NAS181 (10 microM), but not by the 5-HT1A and 5-HT1D antagonists WAY100135 (3 microM) and BRL15572 (10 microM). Sumatriptan also inhibited evoked IPSCs with an IC50 of 261 nM, and reduced the rate, but not the amplitude of spontaneous miniature IPSCs. The sumatriptan (1 microM) induced inhibition of evoked IPSCs was abolished by NAS181 (10 microM) and BRL15572 (10 microM), together, but not separately. 5-HT (10 microM) and sumatriptan (3 microM) also reduced the amplitude of non-NMDA mediated evoked excitatory postsynaptic currents (EPSCs) in all PAG neurons tested.

Conclusion: These results indicate that sumatriptan inhibits GABAergic and glutamatergic synaptic transmission within the PAG via a 5-HT1B/D receptor mediated reduction in the probability of neurotransmitter release from nerve terminals. These actions overlap those of other analgesics, such as opioids, and provide a mechanism by which centrally acting 5-HT1B and 5-HT1D ligands might lead to novel anti-migraine pharmacotherapies.

Show MeSH
Related in: MedlinePlus