neurokinin-a and Headache

Up to now, the cause of most types of headaches is unknown. Why headache starts or why it fades away during hours or a few days is still a mystery. This phenomenon makes headache unique compared to other pain states. For long it has been known that during headache sensory structures in the meninges are activated. But it was not until the last two decades that scientists investigated the physiology of the sensory innervation of the meninges. Animal models and in vitro preparations have been developed to get access to the meninges and to determine the response properties of meningeal afferents. Although animals hardly can tell their pain, blood pressure measurements and observations of behaviour in two models of headache suggest that such animal models are valid and may add remarkable information to our understanding of human headache. Since chemicals and endogenous inflammatory mediators may alter sensory thresholds and responsiveness of neurons, they are putative key molecules in triggering pathophysiological sensory processing. This review briefly summarizes what is known about the chemosensitivity of meningeal innervation.

Topics: Afferent Pathways; Animals; Bradykinin; Calcitonin Gene-Related Peptide; Dinoprostone; Disease Models, Animal; Headache; Humans; Meninges; Neurokinin A; Neuropeptides; Nociceptors; Prostaglandins; Substance P

1. MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. 2. The objective of the present study was to assess the capability of the drug to antagonize the stimulatory effects of neurokinin A (NKA) on gastrointestinal motility, as well as to change the fasting migrating motor complex (MMC). 3. Thirty-four male volunteers were randomized to treatment with either placebo or MEN 11420 in a double-blinded manner. Effects of MEN 11420 (8 mg intravenously) were evaluated as changes in phases I, II and III of MMC, as well as contraction frequency, amplitude and motility index during baseline conditions and during stimulation of motility using NKA (25 pmol kg(-1) min(-1) intravenously). 4. NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. 5. MEN 11420 effectively antagonized the motility-stimulating effects of NKA. MEN 11420 reduced the phase II-stimulating effect of NKA. In addition, the stimulatory effect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not affect the characteristics of MMC during saline infusion. 6. Plasma levels of MEN 11420 peaked during the first hour after infusion and decreased to less than half during the first 2 h. 7. In conclusion, intravenous MEN 11420 effectively inhibited NKA-stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects.

Topics: Abdominal Pain; Adolescent; Adult; Double-Blind Method; Flushing; Gastrointestinal Motility; Headache; Humans; Infusions, Intravenous; Intestine, Small; Male; Middle Aged; Muscle Contraction; Myoelectric Complex, Migrating; Nausea; Neurokinin A; Peptides, Cyclic; Receptors, Neurokinin-2; Sodium Chloride; Time Factors; Vomiting

Primary trigeminal neurons of the trigeminal ganglion (TG) innervate major parts of the face and head, including the dura. Electrical stimulation of the TG at specific parameters, can activate its nociceptive neurons and may serve as an experimental pain model. Markowitz [J. Neurosci. 7 (1987) 4129] reported that electrical stimulation of the trigeminal ganglion (TG) causes extravasation of plasma proteins from venules of the trigeminally innervated domain possibly due to the release of vasoactive substances. Neurogenic inflammation (vasodilatation, plasma protein extravasation, release of vasoactive peptides) in dura may serve as one of the possible pathomechanisms underlying vascular head pain [Moskowitz, Ann. Neurol. 16 (1984) 157]. We performed a unilateral electrical stimulation (7.5 Hz, 5 ms, 0.8-1.4 mA for 5 min) of the TG in rat, to induce a neurogenic inflammation in the peripheral trigeminal domain including the dura, looking for calcitonin gene related peptide (CGRP), substance P (SP) and neurokinin A (NKA) immunoreactivity (IR) in the caudal trigeminal nucleus (CTN) into which massive central trigeminal processes terminate. Here, we show patchy depletion(s) of CGRP-, SP- and NKA-IRs in the contralateral CTN of the rat in addition to their ipsilateral depletion. Such depletion is due to the release of these neuropeptides in the CTN leading to the activation of bilateral trigeminal nociceptive pathway. These data afford the possibility that under specific frequencies (which may roughly correlate to the intensity of the painful stimulus) and/or specific intensities (may correlate to specific areas of the peripheral trigeminal domain) of stimulation, activation of one side of the TG may activate bilateral trigeminal nociceptive pathway leading to the perception of an ill localized/generalized pain or headache rather than a unilateral one.

Topics: Animals; Calcitonin Gene-Related Peptide; Electric Stimulation; Female; Functional Laterality; Headache; Male; Neurokinin A; Pain; Rats; Rats, Wistar; Substance P; Trigeminal Ganglion; Trigeminal Nucleus, Spinal