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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: 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.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.

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.

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Sumatriptan decreases the rate, but not the amplitude of miniature IPSCs. (A) Time course of miniature IPSC (mIPSC) rate during superfusion of sumatriptan (3 μM) and SR95531 (10 μM). (B) Raw current traces of miniature IPSCs before (control) and during superfusion of sumatriptan (3 μM). (C) Averaged traces of miniature IPSCs before and during superfusion of sumatriptan (3 μM). Cumulative distribution plots of miniature IPSC (D) inter-event interval and (E) amplitude, before and during sumatriptan (3 μM). (F) Bar chart of the mean rate and amplitude of miniature IPSCs in the presence of sumatriptan (3 μM), expressed as a percentage of the pre-sumatriptan level, ** denotes p < 0.01. Traces in (A – E) are from the same neuron.
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Figure 6: Sumatriptan decreases the rate, but not the amplitude of miniature IPSCs. (A) Time course of miniature IPSC (mIPSC) rate during superfusion of sumatriptan (3 μM) and SR95531 (10 μM). (B) Raw current traces of miniature IPSCs before (control) and during superfusion of sumatriptan (3 μM). (C) Averaged traces of miniature IPSCs before and during superfusion of sumatriptan (3 μM). Cumulative distribution plots of miniature IPSC (D) inter-event interval and (E) amplitude, before and during sumatriptan (3 μM). (F) Bar chart of the mean rate and amplitude of miniature IPSCs in the presence of sumatriptan (3 μM), expressed as a percentage of the pre-sumatriptan level, ** denotes p < 0.01. Traces in (A – E) are from the same neuron.

Mentions: In the presence of TTX (300 nM), CNQX (5 μM) and strychnine (5 μM) spontaneous miniature IPSCs were observed which were abolished by SR95531 (10 μM, n = 4) (Figure 6a). Sumatriptan (3 μM) produced a reduction in the rate of miniature IPSCs in the majority of PAG neurons tested (Figure 6a, b, f, p = 0.007, n = 7). The reduction in miniature IPSC rate produced by sumatriptan only partially reversed after a lengthy washout period (Figure 6a), as observed for evoked IPSCs. The sumatriptan induced reduction in miniature IPSC rate was associated with a rightward shift in the cumulative probability distribution of miniature IPSC inter-event intervals (Figure 6d). By contrast, sumatriptan did not produce a change in the amplitude (p = 0.2) or kinetics of miniature IPSCs, or in the cumulative probability distributions of mIPSC amplitudes (Figure 6c, e, f).


Sumatriptan inhibits synaptic transmission in the rat midbrain periaqueductal grey.

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

Sumatriptan decreases the rate, but not the amplitude of miniature IPSCs. (A) Time course of miniature IPSC (mIPSC) rate during superfusion of sumatriptan (3 μM) and SR95531 (10 μM). (B) Raw current traces of miniature IPSCs before (control) and during superfusion of sumatriptan (3 μM). (C) Averaged traces of miniature IPSCs before and during superfusion of sumatriptan (3 μM). Cumulative distribution plots of miniature IPSC (D) inter-event interval and (E) amplitude, before and during sumatriptan (3 μM). (F) Bar chart of the mean rate and amplitude of miniature IPSCs in the presence of sumatriptan (3 μM), expressed as a percentage of the pre-sumatriptan level, ** denotes p < 0.01. Traces in (A – E) are from the same neuron.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: Sumatriptan decreases the rate, but not the amplitude of miniature IPSCs. (A) Time course of miniature IPSC (mIPSC) rate during superfusion of sumatriptan (3 μM) and SR95531 (10 μM). (B) Raw current traces of miniature IPSCs before (control) and during superfusion of sumatriptan (3 μM). (C) Averaged traces of miniature IPSCs before and during superfusion of sumatriptan (3 μM). Cumulative distribution plots of miniature IPSC (D) inter-event interval and (E) amplitude, before and during sumatriptan (3 μM). (F) Bar chart of the mean rate and amplitude of miniature IPSCs in the presence of sumatriptan (3 μM), expressed as a percentage of the pre-sumatriptan level, ** denotes p < 0.01. Traces in (A – E) are from the same neuron.
Mentions: In the presence of TTX (300 nM), CNQX (5 μM) and strychnine (5 μM) spontaneous miniature IPSCs were observed which were abolished by SR95531 (10 μM, n = 4) (Figure 6a). Sumatriptan (3 μM) produced a reduction in the rate of miniature IPSCs in the majority of PAG neurons tested (Figure 6a, b, f, p = 0.007, n = 7). The reduction in miniature IPSC rate produced by sumatriptan only partially reversed after a lengthy washout period (Figure 6a), as observed for evoked IPSCs. The sumatriptan induced reduction in miniature IPSC rate was associated with a rightward shift in the cumulative probability distribution of miniature IPSC inter-event intervals (Figure 6d). By contrast, sumatriptan did not produce a change in the amplitude (p = 0.2) or kinetics of miniature IPSCs, or in the cumulative probability distributions of mIPSC amplitudes (Figure 6c, e, f).

Bottom Line: 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.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.

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