Methionine‐Enkephalin in Migraine and Tension Headache. Differences Between Classic Migraine, Common Migraine and Tension Headache, and Changes During Attacks.

Ferrari, Michel D.; Odink, J.; Frölich, Marijke; Portielje, Johanneke E.A.; Bruyn, G.W.

doi:10.1111/j.1526-4610.1990.hed3003160.x

Cited by 12 publications

(6 citation statements)

References 18 publications

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“…As DENKI analgesic effect depends on extracellular concentrations of enkephalins, these data suggest that headache may be associated with high levels of extracellular enkephalins. In accordance, several studies have shown that acute migraine episodes are accompanied by significant increases in plasma Met-enkephalin levels, which return to normal levels after a pain-free period of several days up to 3 weeks 14,15 . Changes in circulating enkephalin levels could be viewed as an endogenous pain modulation mechanism alleviating the severity of migraine attacks 14 .…”

Section: Discussionsupporting

confidence: 69%

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model

Descheemaeker

Poras

Wurm

et al. 2022

Brain

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The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from their rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioral testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate. In naive rats, single or repeated administration of PL37 or vehicle had no effect on cephalic mechanical sensitivity. However, single oral PL37 treatment effectively inhibited isosorbide dinitrate-induced acute cephalic mechanical hypersensitivity. Single intravenous but not oral PL37 administration inhibited chronic cephalic mechanical hypersensitivity. Daily oral administration of PL37 prevented cephalic mechanical hypersensitivity and decreased touch-induced c-Fos expression in trigeminocervical complex following repeated isosorbide dinitrate administration. These data reveal the therapeutic potential of the dual enkephalinase inhibitor PL37 as an acute and prophylactic treatment for migraine. Protecting enkephalins from their degrading enzymes therefore appears as an innovative approach to treat migraine.

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Section: Discussionsupporting

confidence: 69%

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model

Descheemaeker

Poras

Wurm

et al. 2022

Brain

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“…Aspartate X Blood levels increased in migraine with aura 167,168 Probably a reflection of increased neuronal activity (CNS or peripheral?) CCK X Possible pain production via vasodilatation Endogenous opiates X Blood levels of enkephalin may rise during headache 169,170 Possibly a marker of an activated descending pain control system "Autacoids" and non-neuronal biochemical markers Histamine X Histamine produces vascular-type headaches; 34 histamine levels rise in migraine 171 constrained within the rigid cranium. Perhaps such stretching might only occur in the absence of this constraint -this might explain the observations of Goltman 1 and Lance.…”

Section: Dural and Vascular Mechanoreceptorsmentioning

confidence: 99%

The Lack of Peripheral Pathology in Migraine Headache

Lambert

2010

Headache

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This article reviews the baffling problem of the pathophysiology behind a peripheral genesis of migraine pain--or more particularly the baffling problem of its absence. I examine a number of pathophysiological states and the effector mechanisms for these states and find most of them very plausible and that they are all supported by abundant evidence. However, this evidence is mostly indirect; to date the occurrence of any of the presumed pathological states has not been convincingly demonstrated. Furthermore, there is little evidence of increased trigeminal sensory traffic into the central nervous system during a migraine attack. The article also examines a number of observations and experimental programs used to bolster a theory of peripheral pathology and suggests reasons why they may in fact not bolster it. I suggest that a pathology, if one exists, may be in the brain and even that it may not be a pathology at all. Migraine headache might just happen because of random noise in an exquisitely sensitive and complex network. The article suggests an experimental program to resolve these issues.

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“…Several studies have accordingly shown that acute migraine episodes are accompanied by significant increases in plasma Met-enkephalin levels, which return to normal levels after a painfree period of several days up to 3 weeks. 28,29 Changes in circulating enkephalin levels could be viewed as an endogenous pain modulation mechanism alleviating the severity of migraine attacks. 28 In this context, the effect of PL37, by enhancing the endogenous mechanism of pain modulation, may provide a more physiological tool to reduce pain.…”

Section: Effect Of Pl37 On Cephalic Mhmentioning

confidence: 99%

Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine

Rossignol,

Ouimet,

Poras

et al. 2024

Headache

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ObjectiveThe aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect.BackgroundCombination treatment is frequently used to improve the therapeutic efficacy of drugs. The co‐administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co‐administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5‐HT1B/1D receptor agonist.MethodsWe investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37.ResultsSumatriptan as well as PL37 each produced a dose‐dependent inhibition of ISDN‐induced cephalic MH. Median effective dose (ED50) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04.ConclusionThese results suggest that PL37 acts synergistically with sumatriptan to produce an anti‐allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine.Plain Language SummaryThere have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model.

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Methionine‐Enkephalin in Migraine and Tension Headache. Differences Between Classic Migraine, Common Migraine and Tension Headache, and Changes During Attacks.

Cited by 12 publications

References 18 publications

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model

The Lack of Peripheral Pathology in Migraine Headache

Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine

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