Decentralization monoamine super-sensitivity of migraine and opiate abstinence: common features and different target mechanisms?

The similarity between opiate withdrawal and migraine (M) has been confirmed regarding increased monoamine sensitivity at the neuromuscular junction of the hand's dorsal vein as well as at the neuraxis where dopamine (DA) supersensitivity was observed. Similarities also included an increase in cAMP levels as a precocious sign in both M and opiate withdrawal. Particular attention has been devoted to the time-course of monoamine supersensitivity in M and in abstinence. It has been found that the maximum level of super-sensitivity occurs in M at the end of the M attack, whereas the maximum super-sensitivity is present at the very beginning of opiate abstinence. The inverse time-course of this phenomenon suggests that it could play some pathophysiological role in inducing the end of the M attack. Conversely, it can represent the expected transient result of a pharmacological denervation which ought to result in a supersensitivity of opioid-dependent neuron during withdrawal. In M, the super-sensitivity is wider, indeed, it involves more receptor types. This could be an indirect proof of the involvement of inhibitory pathways other than the opioidergic one.

The way to serotonergic use and abuse in migraine.

5-HT is currently indicated to play a role in migraine (M). Previously evidenced 5-HT supersensitivity which characterizes M is insufficient to compensate for a possible deficit in 5-HT bioavailability. Inducing a further up-regulation of 5-HT receptor can yield improvement of M syndrome. Chronic treatments of methysergide and propranolol, drugs exerting antagonist action at 5-HT receptors, induced a significant amelioration in 256M sufferers. On the contrary, chronic treatments of ergotamine and sumatriptan, both provided with a 5-HT1 agonist activity, induced a worsening of M in 134 M sufferers. The M worsening was paralleled by an increase in consumption of analgesic drugs. Discussion concerns the effects of the chronically given 5-HT agonists and antagonists as well as the possible receptor mechanism underlying "craving for serotonin" in severe M. The increase of 5-HT supersensitivity evidenced at the end of M attacks is also discussed and its role in determining the interruption of the attack is here suggested.

Inheritable and acquired hyperalgesia associated to abnormal opioid receptor set-up seem to act as opiate addiction preventors.

Hyperalgesia is known to depend on neuroplastic changes chiefly represented by long-term potentiation. These phenomena are proved to depend on excitatory amino acids (EAAs) action at the level of NMDA receptors. This action is known to be related to nitric oxide (NO) release. We found a visceral/vascular hyperalgesia state in migraine (M) sufferers as well as an inheritable systemic hyperalgesia in healthy subjects who are first-degree consanguineous with M sufferers; this type was labelled 'third hyperalgesia'. We discovered that a hyper-increase of plasma L-citrulline, equimolar co-product in the synthesis of NO, characterizes both M sufferers and their first-degree relatives who are exempt from primary headache. A similar pattern never occurred in healthy subjects having both a personal and family history negative for primary headache. We conclude that both 'third hyperalgesia' and a pattern of NO synthase (NOS) hyperactivity seems to be inheritable and can constitute, at least in part, a ground for developing headache. Morphine, proved to be unable to relieve M attack, was given in low doses that caused pain and side-effects in M sufferers only. This outcome seemingly indicates that M sufferers are characterized by a set-up of opioid receptor subtypes different from that of healthy headache-exempts. Following a period of morphine addiction and a withdrawal period, 65.07% of a group of 63 opiate addicts developed M syndrome. All these subjects were first-degree consanguineous relatives of primary headache sufferers. Discussion topics concern the activity of morphine in NO release and the role of NO in sensory transmission of both controls and hyperalgesia sufferers. It is suggested that the inheritable couple consisting of hyperalgesia and NOS hyperactivity can play some role in setting off the pain occurring following morphine in M sufferers.

Modulation of excitatory amino acids pathway: a possible therapeutic approach to chronic daily headache associated with analgesic drugs abuse.

The use of antagonists of N-methyl-D-aspartate (NMDA) receptors, or the administration of inhibitors of the synthesis or of the release of excitatory amino acids, enables the analgesic drug-dependence associated with chronic daily migraine to be overcome without any physical abstinence sign. Follow-up period indicates that negative modulators of excitatory amino-acid function can induce a stable benefit. The persistent benefit is seemingly due to an inhibitory effect on the process underlying the hyperalgesia state which is a crucial feature of migraine. It can also be suggested that the antagonist activity at NMDA receptor might play a role in very severe non-opioid analgesic drug dependence.

[Headache caused by analgesic and/or ergotamine abuse]. / Cefalee da abuso di analgesici e/o ergotamina.

Headache induced by ergotamine-abuse was described 40 years ago. More recently there is ample evidence suggesting that chronic headache may also be provoked by analgesic abuse. A recent Classification of the International Headache Society has defined this kind of headache as an autonomous disease. It consists in a daily chronic headache with paroxysmal attacks associated with daily or almost daily assumption of analgesics and/or ergotamine. It is debated whether the term "abuse" or "dependence" is correct. Almost 5% of patients of the Headache Centres in Italy were found to be drug abusers. Most of these patients originally suffered from migraine. The therapeutic approach consists in hospitalization, withdrawal of analgesics and/or ergotamine, treatment of the withdrawal headache (which appears within 48 hours and lasts even 1-2 weeks) and finally in a prophylactic therapy. Although several treatments have been suggested for the abstinence syndrome, only fluid replacement, antiemetics, hypnotic-sedative drugs and rarely mild analgesics are necessary. A review of the literature shows the following success rates in the relief of the headache: above 50% relief in more than 60% of patients within a follow up period of 1 to 3.5 years as mean. Even if caffeine and barbiturates, which are often contained in the analgesic and ergotamine preparations, might be considered the cause of the abuse and withdrawal syndrome, they don't seem to play a fundamental role in this syndrome. An impairment of the central antinociceptive system was hypothesized to be involved in the pathogenesis of the headache associated with analgesic and/or ergotamine abuse. Recently there has been evidence of a possible hyposensitivity of the adrenergic and serotoninergic receptors of the central nervous system. It is still to be proved whether drug abuse is the cause or the consequence of the headache chronicization. The remarkable improvement of headache after analgesic withdrawal suggests a causal factor.

Reduced serotonin vascular sensitivity in ergotamine abusers.

The action of ergotamine on the 5-hydroxytryptamine (5-HT) venous sensitivity was studied in ergotamine abuser and non-abuser migraine patients. Ergotamine abusers showed reduced 5-HT hand vein contraction during abuse, compared to seven days after ergotamine withdrawal. In non-ergotamine users, the 5-HT venoconstriction was not significantly modified 12 h after a single intramuscular ergotamine (0.25 mg) administration. Even the administration of ergotamine locally into the vein did not change the venospasm of 5-HT given acutely in the same vein. Therefore, it seems that the 5-HT antagonism does not contribute to the therapeutic effect of ergotamine during the migraine attack. Moreover, the reduced 5-HT responsiveness during ergotamine abuse may possibly be compatible with the chronic headache present in some abusers, the withdrawal headache attacks and the abuse itself.

Effects of calcium antagonists on serotonin and noradrenaline venoconstriction in humans.

The activity of some calcium antagonists on 5-hydroxytryptamine (5HT) and noradrenaline-induced venoconstriction has been evaluated in humans. Oral doses of nimodipine, 30 mg, and nifedipine, 10 mg, but not of verapamil, 80 mg, and flunarizine, 10 mg, inhibit 5HT-induced venoconstriction of the dorsal hand vein. Nimodipine, but not verapamil and flunarizine, inhibit noradrenaline-induced venoconstriction as well. Verapamil, locally administered into the hand vein, inhibits 5HT and noradrenaline-induced venoconstriction. These results suggest that only calcium antagonists of the dihydropyridine type have antivenoconstrictive activity in the hand vein at oral clinical doses, whereas verapamil is active only if administered by the intravenous route, which probably produces local plasma concentrations higher than those reached with the oral clinical doses.

Somatostatin: peripheral venoconstrictive activity and interaction with monoamines in man.

The mechanism of somatostatin venoconstriction and tachyphylaxis in the human hand vein in vivo has been investigated. No cross-tachyphylaxis was observed between somatostatin and 5-hydroxytryptamine, noradrenaline, adrenaline, dopamine or tyramine-induced venoconstriction. Somatostatin potentiates the venoconstrictive activity of noradrenaline, adrenaline and dopamine, but not that of 5-hydroxytryptamine and tyramine. Phentolamine antagonizes the somatostatin-induced venoconstriction, whereas methysergide, haloperidol and morphine do not. It is suggested that somatostatin could act on specific receptors in the hand vein, but the mechanism of somatostatin venoconstriction and interaction with vasoactive monoamines remains to be defined.

Enkephalinase and angiotensin converting enzyme activities in human venous and arterial plasma.

Circulating opioids, particularly enkephalins, can act on specific receptors located on the neurovascular sympathetic junction. These peptides are quickly metabolized by enkephalinase and angiotensin converting enzyme (ACE). According to the parallel distribution of enkephalinase with opioid receptors in the rat brain, and its location in the vascular bed, putative differences of enkephalinase and ACE activity between arterial and venous plasma of the same subjects was researched. Venous enkephalinase activity was found to be greater than arterial activity. No arterovenous differences were present in ACE activity. The activities of both enzymes presented a positive correlation between venous and arterial plasma in the same subjects. The arterovenous difference in enkephalinase activity supports a release of the enzyme from microvessels.

Venospastic activity of somatostatin in vivo in man: naloxone reversible tachyphylaxis.

When the dorsal hand vein (DHV) is locally injected with somatostatin (SS) it spasms visibly. These spasms can be measured using the computerized venospasm technique. Acute, complete long-lasting tolerance (tachyphylaxis) develops following 2-4 injections of somatostatin. A revival of sensitivity to SS is induced in the fatigued vein by the local injection of naloxone. This suggests that endogenous opioids could participate partially or totally in SS tachyphylaxis. The analgesic effect displayed by somatostatin on the dramatic pain of the cluster attack is quantitatively similar to that of ergotamine; the therapeutic mechanism of both drugs has until now remained undefined.

Impaired 5-hydroxytryptamine tachyphylaxis in migraine.

Tachyphylaxis (TPX) to the spasmogenic activity of 5HT can be demonstrated in vivo in the superficial hand dorsal veins in man by the computerized venotest. The 5HT-TPX is reverted by previous local naloxone administration. Tachyphylaxis to 5HT is usually absent in the migraineur. The restored 5HT spasmogenic effect by naloxone suggests the possibility of local opioid apparatus participation in TPX to 5HT.

Clinical pharmacological aspects of dihydroergotamine timed release: activity on monoamine venospasm.

Using the computerized venotest, it is possible to evaluate both the venospastic activity of the vasoactive monoamines (NA,5-HT, DA) and the effects of the relative agonistic and antagonistic drugs. The ergot-derivatives are 5-HT and NA agonists at low doses, and are 5-HT antagonists at high doses. Dihydroergotamine timed release (DHE-TR) administered orally is capable at 12 hours following the last administration of producing a significant increase of 5-HT and NA venospasm. It is hypothesized that 12 hours after the last administration of DHE-TR, hematic concentrations, corresponding to clinical and therapeutic levels, capable of potentiating the monoamine venospasm still exists.

Naloxone reversal of 5-hydroxytryptamine tachyphylaxis in humans.

The dorsal hand vein, a suitable substrate for testing the effects of spasmogenic amines in vivo, exhibits a rapid tachyphylaxis to 5-hydroxytryptamine (5-HT)-induced vasoconstriction in healthy subjects. In the tachyphylactic vein, naloxone promptly restores and sometimes potentiates the sensitivity to 5-HT. The local opioid system could be excited by the 5-HT-induced release of noradrenaline (NA) into the neuromuscular junction, thereby participating in the 5-HT tachyphylaxis. Naloxone, antagonizing this mechanism, restores the 5-HT spasm. Therefore, the 5-HT tachyphylaxis could be due to an increased opioid modulation and not (or perhaps partially) to a depletion of the NA in the sympathergic neuron.

Monoamine sensitivity of smooth muscle in vivo in nociception disorders.

A significant degree of supersensitivity to 5-HT and DA was detected when carrying out the computerized venotest on migraine patients during an attack. A similar supersensitivity was observed during morphine abstinence and naloxone-precipitated withdrawal in addicts. Mild abstinence after slight and short morphine treatment provoked monoamine supersensitivity in volunteers. In these conditions, the administration of morphine inhibited the 5-HT and DA supersensitivity. In spontaneous central panalgesia, monoamine supersensitivity is detectable, as well as in panalgesia induced in headache sufferers by means of PCPA 5-HT deprivation. By means of the venotest, the ergot derivatives were confirmed as being partial 5-HT agonists. These drugs can also carry out their therapeutic activity by potentiating 5-HT at a central level in 5-HT-deficient neurons. The presence of opiate receptors in the human vein is stressed. The high supersensitivity of the venous smooth muscle to 5-HT and DA both in headache and systemic pain sufferers and during morphine withdrawal suggests a pathophysiological analogy between these conditions.

Dopamine and 5-HT supersensitivity in nonorganic central pain and in morphine abstinence: fortuitous or renal analogy?

Unexplained pain, such as central panalgesia, might be the most common clinical expression of a deficiency, central in nature, of the endorphin system. Acute natural opioid deficiency is comparable to morphine withdrawal in addicts characterized by vegetative, psychic disorder and the appearance of pain. An impressive supersensitivity (up to 1000 fold) to dopamine and 5-HT of the smooth muscle (hand dorsal vein: venotest) is detected both in central panalgesia sufferers and in addicts during spontaneous (withdrawal) or pharmacological (naloxone) abstinence. A 5-HT and dopamine supersensitivity, of less intensity, however, (10-30 fold), is found during migraine attacks: on these occasions, morphine-like factors in CSF appear reduced or undetectable, reinforcing the chemical analogy between morphine abstinence and migraine attacks. In the present study, evidence of opiate receptors in the human vein is also provided: 5-HT venospasms, inhibited by morphine, promptly emerge when naloxone is inoculated locally.

Morphine abstinence and serotonin supersensitivity in man: analogies with the mechanism of migraine?

Supersensitivity to serotonin during migraine attack has been previously observed. Since the attack has been attributed to a critical lowering of morphine-like factors, we can expect serotonin supersensitivity during morphine abstinence. Slight signs of morphine abstinence have also been induced in volunteers after mild (10-24 mg/day) and limited (3 days) treatment. To evaluate the sensitivity to serotonin, dopamine, noradrenaline, and tyramine in the smooth muscle of the hand dorsal vein, in vivo, the computerized venotest was applied before, during, and 24 h after withdrawal of morphine. Venous sensitivity to serotonin and dopamine (but not to noradrenaline and tyramine) increased 10- to 20-fold after morphine withdrawal. Venous monoamine supersensitivity in morphine abstinence, similar to that observed during migraine attacks, could be indirect evidence of an analogous mechanism in both conditions.