Tachykinins and neuropsychiatric disorders

The classical tachykinins, substance P, neurokinin A and neurokinin B are predominantly found in the nervous system where they act as neurotransmitters and neuromodulators. Their respective preferred receptors are NK1, NK2, and NK3 receptors. The presence of substance P in nociceptive primary afferent neurons, electrophysiological studies showing that it activated neurons in the dorsal horn of the spinal cord, and behavioral studies in animals, supported the concept that substance P was an important transmitter in the nociceptive pathway. It was therefore surprising that non-peptide NK1 receptor antagonists were ineffective as analgesics in clinical pain conditions. Nevertheless, the discovery that NK1 receptor antagonists had antidepressant activity led to renewed interest in these antagonists. It is disappointing that clinical trials of MK869 (aprepitant) for depression were suspended. The future of NK1 receptor antagonists as antidepressant drugs will depend on the outcome of clinical trials with other NK1 receptor antagonists. NK1 receptor antagonists were also found to be effective antiemetics, and aprepitant has recently become available for the treatment of chemotherapy induced emesis. Although less is known of the potential of NK2 and NK3 receptor antagonists, recent trials of NK 3 receptor antagonists have shown efficacy in schizophrenia. The discovery of a new family of tachykinins, the hemokinins and endokinins, which acts on NK1 receptors and has potent effects on immune cells, has implications for the clinical use of NK1 receptor antagonists. Thus specific therapeutic strategies may be required to enable NK1 receptor antagonists to be introduced for treatment of neuropsychiatric disorders

Responses of the rat cardiovascular system to substance P, neurotensin and bombesin

The carotid arterial blood pressure and heart rate responses to intravenous injections of substance P, neurotensin and bombesin were compared in anaesthetized rats. In rats anaesthetized with urethane neurotensin produced only a fall in blood pressure but in rats anaesthetized with sodium thiobutabarbitone, the fall was preceded by a transient rise in blood pressure. The reason for the different responses to neurotensin with the two anaesthetics was not investigated. The hypotensive effect of neurotensin observed with both anaesthetics was abolished by mepyramine and therefore appeared to be mediated by action on H receptors either of neurotensin directly or of histamine released. On the other hand, catecholamines might be implicated in the pressor response to neurotensin observed in rats anaesthetized with sodium thiobutabarbitone since it was reduced by phentolamine and hexamethonium. Low doses of substance P produced a depressor response which was not inhibited by the antagonists tested. At higher doses marked tachycardia occurred and the depressor response was less and was often followed by a pressor response. The tachycardia was abolished by propranolol but not by cervical cord section or by hexamethonium. Bombesin produced a pressor response which was unaffected by hexamethonium but was reversed to depressor by phentolamine. This depressor response to bombesin was abolished by propranolol. It was concluded that substance P produced a depressor response by action on its own specific receptors and tachycardia by catecholamine release whereas neurotensin and bombesin produced cardiovascular actions which were mediated entirely by amine release

Effect of catecholamines on oedema induced by inflammatory agents in the rat

The effect of intracutaneous adrenaline and noradrenaline (5 × 10 and 5 × 10 mol) was examined on the oedema (Evans blue dye leakage) response of rats to several inflammatory agents. The catecholamines reduced the oedema response to all agents tested except prostaglandin E (PGE) which was significantly potentiated by noradrenaline (5 × 10 mol), and a combination of bradykinin 5 × 10 mol with PGE 5 × 10 mol which was not significant affected by any dose of catecholamine. Adrenaline was more effective than noradrenaline in reducing oedema produced by 5-hydroxytryptamine (5HT) and histamine and by agents which release these amines (compound 48 80, dextran and antigen challenge with egg albumin in sensitized rats), but not noradrenaline was more potent against bradykinin-induced oedema. The inhibitory effect of catecholamines against oedema produced by histamine and 5HT was abolished by a combination of phentolamine and propranolol. It was concluded that the oedema-inhibiting effect of catecholamines is due to α- and β-adrenoreceptor mediated actions

Localization of NK1 and NK3 receptors in guinea-pig brain

In this study the localizations of tachykinin neurokinin-1 (NK1) and neurokinin-3 (NK3) receptors in the guinea-pig brain are described. In agreement with studies in rat and human brain, the neurons that exhibited the most marked NK1 receptor immunoreactivity were found in the dorsomedial caudate putamen. NK1 receptors were also widely distributed in diencephalic structures and in the mid and hind brain. NK3 receptors were distributed in both superficial and deep layers of the cortex and many appeared to be located on cells with astrocyte-like morphology in the glia limitans. In several regions including the thalamus, hypothalamus, amygdala, periaqueductal gray, substantia nigra and area postrema, both NK1 and NK3 immunoreactivity were found. The present study revealed that tachykinin receptors are widely distributed in the guinea-pig central nervous system

The effect of single or repeated applications of "therapeutic" ultrasound on plasma extravasation during silver nitrate induced inflammation of the rat hindpaw ankle joint in vivo

The effect of "therapeutic" ultrasound upon plasma extravasation during the inflammatory process induced in the rat hindpaw ankle by intra-articular injection of silver nitrate was investigated in two series of experiments. Both series utilised three ultrasonic frequencies, 0.75, 1.5, and 3.0 MHz, and two pulse ratios, mark:space 1:4 and 1:1. Series 1 examined the effect of two durations of ultrasound, 1 or 2 min, administered once only, and series 2 examined the effect of single or repeated insonations of 1 min duration. It was found that ultrasound treatment increased plasma extravasation compared to controls during the first 24 hr, but later reduced it significantly compared to controls. This secondary effect of reduction in plasma extravasation was delayed in animals given three insonations, this number of insonations being found to prolong the plasma extravasation phase

Mediators of the Plasma Extravasation Response to Silver Nitrate in the Rat Skin, Subplantar Region and Ankle Joint

Abstract— Plasma extravasation responses to silver nitrate (AgNO), histamine, 5‐hydroxytryptamine (5‐HT), bradykinin and prostaglandin E (PGE) in the abdominal skin, hindpaw ankle joint and subplantar region of rats have been investigated using the Evans blue dye leakage technique. All substances tested produced plasma extravasation and combination of low doses (5 × 10mol) of either histamine or bradykinin with PGE, (5 × 10mol) exhibited potentiation of responses of all regions. Responses to AgNO (1 × 10mol) were significantly reduced by the H receptor antagonist, mepyramine, only in the abdominal skin, but the H receptor antagonist metiamide reduced the responses at subplantar and ankle joint regions. Indomethacin significantly reduced the AgNO responses at the ankle joint only, but aprotinin reduced it at the other two regions. In rats pretreated with a combination of all antagonists the residual plasma extravasation response to AgNO was very small, indicating that the response could be almost totally accounted for by the combined actions of mast cell amines, kinins and prostanoids. The finding that prostanoids played a major role in the plasma extravasation response of the rat ankle joint to AgNO indicated that this model would be useful for the screening of non‐steroidal anti‐inflammatory drugs. 1989 Royal Pharmaceutical Society of Great Britai

The effects of haloperidol treatment on the distribution of NK1 receptor immunoreactive neurons in guinea-pig brain (Short communication)

Previous studies have observed increased tachykinin NK1 receptor immunoreactivity (NK1-IR) in the prefrontal cortex in subjects with schizophrenia. Since the subjects were medicated the possibility of a treatment effect could not be excluded. Thus, the present study was undertaken to determine the effect of chronic treatment with the antipsychotic drug, haloperidol, on the distribution of NK1-IR neurons in the guinea-pig brain. Guinea pigs were treated each day for 21 days with either haloperidol (1 mg/kg) or vehicle and the brains were then processed for immumohistochemistry using an NK1 receptor-specific polyclonal antibody. NK1-IR neurons and fibres were abundant in the forebrain cortex and caudate putamen and more sparsely distributed in a number of other brain regions. The relative density of NK1-IR neurons was significantly increased in the forebrain cortex, but not in the caudate putamen in guinea pigs treated with haloperidol. This study has shown that haloperidol causes region-specific changes to the density of NK1-IR neurons. Whether these changes are related to the therapeutic effects or to the side effects of haloperidol in individuals with schizophrenia, remains to be determined. (c) 2005 Elsevier Ireland Ltd. All rights reserved