Indomethacin, alone and combined with prochlorperazine and caffeine, but not sumatriptan, abolishes peripheral and central sensitization in in vivo models of migraine

Abstract

M igraine is a common, multifactorial, neurovascular disorder, characterized by recurrent disabling attacks of moderate to severe headache, nausea, vomiting, photophobia, and phonophobia, and also, in up to one third of patients, neurologic aura symptoms. 12 It is known that migraine is characterized by a state of central neuronal hyperexcitability, 30 which involves overactivity of the excitatory amino acids. Higher concentrations of excitatory amino acids (mainly glutamic and aspartic acid) were observed in the cerebrospinal fluid, 23 in the saliva, 26 in the plasma, 2,13 and in the platelets 9 of patients with migraine.Recently it has been proposed that the throbbing pain of migraine, which is the pulsating pain aggravated by routine physical activities, is mediated by sensitization of peripheral trigeminovascular neurons, and that cutaneous allodynia (CA) of migraine, which means pain resulting from a non-noxious stimulus to normal skin, is mediated by sensitization of central trigeminovascular neurons. 4,22 The development of hyperalgesia has been shown after the injection of kainic acid. The hyperalgesic effect of kainic acid appears to be mediated by activity at aminomethylisoxazole-propionic acid/kainate receptors that are located outside the spinal cord, perhaps on primary afferents in trigeminal ganglia. 27 Intraperitoneal injection of kainic acid induces a persistent hyperalgesia in mice and rats. 18 Glutamate, an excitatory neurotransmitter, produces

Effect of modulation of serotonergic, cholinergic, and nitrergic pathways on murine fundic size and compliance measured by ultrasonomicrometry

“…The doses used were 0.2-0.4 mg/kg atropine, 0.15 mg/kg bethanechol, 0.1-0.3 mg/kg sumatriptan, 0.1-0.3 mg/kg buspirone, 0.03 mg/kg nitroglycerin, and 0.5-1.5 mg/kg L-NNA. Doses were selected based on our previous work and on published data (5,6,10,15,17,20,26,42).…”

Rheological and textural properties of microemulsion-based polymer gels with indomethacin

“…It was synthesized and introduced to the pharmaceutical market in the 1960s 29 . Since then IND has been successfully applied in rheumatoid arthritis 30 , osteoarthritis 31 , gout attacks 32 , migraine and menstrual pain 33,34 . However, non-selective inhibition of both cyclooxygenase 1 and 2 isoenzymes (COX-1 and COX-2) is the cause of numerous side effects observed after oral administration of IND 31 .…”

The central analgesia induced by antimigraine drugs is independent from Gi proteins: superiority of a fixed combination of indomethacin, prochlorperazine and caffeine, compared to sumatriptan, in an in vivo model

“…The efficacy of indomethacin in the treatment of migraine and other primary headaches might be due to its central analgesic activity [5], its ability to abolish peripheral and central hyperalgesia [6–8], its vasoconstrictive effect on cerebral vessels [9–11] and its ability to inhibit neurogenic inflammation [12]. The mechanism of action of prochlorperazine in migraine could be attributed to its central cholinergic analgesic effect [13] and to its ability to abolish hyperalgesia [6, 7]. Caffeine is used as an effective analgesic adjuvant in various analgesic combinations.…”

“…Moreover, Indoprocaf, but not sumatriptan, administered i.p. at sub-analgesic doses in mice, was able to abolish peripheral and central sensitization [7]. …”