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Dear all
I was reading the chapter on migraine in Harrison's Internal Medicine, and got confused by some things - I was hoping some of you could explain it to me.
(it may seem that I ask a lot of questions, since my last thread is still near the top - but I asked the question 2 weeks ago, and the thread got bumped up by a few guys arguing with each other..)
Here is the paragraph from Harrison's
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The Sympathetic Nervous System in Migraine
Alterations occur within the sympathetic nervous system (SNS) of migraineurs before, during, and between migraine attacks. Factors that activate the SNS are all triggers for migraine. Specific examples include environmental changes (e.g., stress, sleep patterns, hormonal shifts, hypoglycemia) and agents that cause release and a secondary depletion of peripheral catecholamines (e.g., tyramine, phenylethylamine, fenfluramine, m-chlorophenylpiperazine, and reserpine).
By contrast, effective therapeutic approaches to migraine share an ability to mimic and/or enhance the effects of norepinephrine in the peripheral SNS. For example, norepinephrine itself, sympathomimetics (e.g., isometheptene), monoamine oxidase inhibitors (MAOIs), and reuptake blockers alleviate migraine. Dopamine antagonists, prostaglandin synthesis inhibitors, and adenosine antagonists are pharmacologic agents effective in the acute treatment of migraine. These drugs block the negative feedback inhibition or norepinephrine release induced by endogenous dopamine, prostaglandins, and adenosine. Therefore, migraine susceptibility may relate to genetically based variations in the ability to maintain adequate concentrations of certain neurotransmitters within postganglionic sympathetic nerve terminals. This hypothesis has been called the empty neuron theory of migraine.
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So it says that factors which activate the SNS are triggers for migraine (the red text). But then it says that norepinephrine and symphathomimetics can relieve migraine (the blue text).
Isn't this a contradiction? Norepinephrine and sympathomimetics will activate the SNS, so they should be triggers for migraine, not treatment..
I think the keyword here may be 'peripheral' SNS. But I still don't understand what significance it has.
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5-Hydroxytryptamine in Migraine
Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin) in migraine. Approximately 40 years ago, methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced as the first drug capable of preventing migraine attacks. Subsequently, it was found that platelet levels of 5-HT fall consistently at the onset of headache and that drugs that cause 5-HT to be released may trigger migrainous episodes. Such changes in circulating 5-HT levels proved to be pharmacologically trivial, however, and interest in the humoral role of 5-HT in migraine declined.
More recently, interest in the role of 5-HT in migraine has been renewed due to the introduction of the triptan class of antimigraine drugs. The triptans are designed to stimulate selectively a particular subpopulation of 5-HT receptors. At least 14 specific 5-HT receptors exist in humans. The triptans (e.g., naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are potent agonists of 5-HT1B, 5-HT1D, and 5-HT1F receptors and are less potent at 5-HT1A and 5-HT1E receptors. A growing body of data indicates that the antimigraine efficacy of the triptans relates to their ability to stimulate 5-HT1B receptors, which are located on both blood vessels and nerve terminals. Selective 5-HT1D receptor agonists have, thus far, failed to demonstrate clinical efficacy in migraine. Triptans that are weak 5-HT1F agonists are also effective in migraine; however, only 5-HT1B efficacy is currently thought to be essential for antimigraine efficacy.
-------------------------------------------------------------
Here is another mystery. They are saying methysergide, which is a 5-HT antagonist, was effective in treating symptoms of migraine (the red text). But later, they are saying the triptan drugs, which are 5-HT agonists, were recently introduced as treatments for migraine..
Again, the word 'peripheral' seems to be important (methyserguide was found to antagonise peripheral actions of 5-HT)
Any thoughts?
I was reading the chapter on migraine in Harrison's Internal Medicine, and got confused by some things - I was hoping some of you could explain it to me.
(it may seem that I ask a lot of questions, since my last thread is still near the top - but I asked the question 2 weeks ago, and the thread got bumped up by a few guys arguing with each other..)
Here is the paragraph from Harrison's
-------------------------------------------------------------
The Sympathetic Nervous System in Migraine
Alterations occur within the sympathetic nervous system (SNS) of migraineurs before, during, and between migraine attacks. Factors that activate the SNS are all triggers for migraine. Specific examples include environmental changes (e.g., stress, sleep patterns, hormonal shifts, hypoglycemia) and agents that cause release and a secondary depletion of peripheral catecholamines (e.g., tyramine, phenylethylamine, fenfluramine, m-chlorophenylpiperazine, and reserpine).
By contrast, effective therapeutic approaches to migraine share an ability to mimic and/or enhance the effects of norepinephrine in the peripheral SNS. For example, norepinephrine itself, sympathomimetics (e.g., isometheptene), monoamine oxidase inhibitors (MAOIs), and reuptake blockers alleviate migraine. Dopamine antagonists, prostaglandin synthesis inhibitors, and adenosine antagonists are pharmacologic agents effective in the acute treatment of migraine. These drugs block the negative feedback inhibition or norepinephrine release induced by endogenous dopamine, prostaglandins, and adenosine. Therefore, migraine susceptibility may relate to genetically based variations in the ability to maintain adequate concentrations of certain neurotransmitters within postganglionic sympathetic nerve terminals. This hypothesis has been called the empty neuron theory of migraine.
-------------------------------------------------------------
So it says that factors which activate the SNS are triggers for migraine (the red text). But then it says that norepinephrine and symphathomimetics can relieve migraine (the blue text).
Isn't this a contradiction? Norepinephrine and sympathomimetics will activate the SNS, so they should be triggers for migraine, not treatment..
I think the keyword here may be 'peripheral' SNS. But I still don't understand what significance it has.
-------------------------------------------------------------
5-Hydroxytryptamine in Migraine
Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin) in migraine. Approximately 40 years ago, methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced as the first drug capable of preventing migraine attacks. Subsequently, it was found that platelet levels of 5-HT fall consistently at the onset of headache and that drugs that cause 5-HT to be released may trigger migrainous episodes. Such changes in circulating 5-HT levels proved to be pharmacologically trivial, however, and interest in the humoral role of 5-HT in migraine declined.
More recently, interest in the role of 5-HT in migraine has been renewed due to the introduction of the triptan class of antimigraine drugs. The triptans are designed to stimulate selectively a particular subpopulation of 5-HT receptors. At least 14 specific 5-HT receptors exist in humans. The triptans (e.g., naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are potent agonists of 5-HT1B, 5-HT1D, and 5-HT1F receptors and are less potent at 5-HT1A and 5-HT1E receptors. A growing body of data indicates that the antimigraine efficacy of the triptans relates to their ability to stimulate 5-HT1B receptors, which are located on both blood vessels and nerve terminals. Selective 5-HT1D receptor agonists have, thus far, failed to demonstrate clinical efficacy in migraine. Triptans that are weak 5-HT1F agonists are also effective in migraine; however, only 5-HT1B efficacy is currently thought to be essential for antimigraine efficacy.
-------------------------------------------------------------
Here is another mystery. They are saying methysergide, which is a 5-HT antagonist, was effective in treating symptoms of migraine (the red text). But later, they are saying the triptan drugs, which are 5-HT agonists, were recently introduced as treatments for migraine..
Again, the word 'peripheral' seems to be important (methyserguide was found to antagonise peripheral actions of 5-HT)
Any thoughts?
