UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of substance P on the sensitivity of nicotinic acetylcholine (ACh) receptors of bullfrog sympathetic ganglion cells and frog skeletal muscle endplate was examined electrophysiologically. The amplitude of ACh-induced postsynaptic potential (ACh potential) and current (ACh current) were reversibly and dose-dependently reduced by substance P at low concentrations (0.42-42 microM). The mean amplitude of the miniature endplate potential (m.e.p.p.) was also reduced by substance P (4.2 microM). Substance P (4.2 microM) shifted the S-shaped dose-response curve of the ACh current downward. A Lineweaver-Burk plot constructed from the dose-response curve revealed that substance P depressed the maximum response (Vmax) without changing the apparent affinity (Km) of ACh for the receptor. Substance P (0.42-42 microM) did not alter the reversal potential of the ACh current of the endplate. The half-decay time of endplate current (e.p.c.) and its voltage-dependency were not altered by substance P in these concentrations. The depression of the ACh current by substance P may not be due to a blockade of the opened channel which has been activated by the preceding combination of ACh with the receptor. These results suggest that substance P suppresses the sensitivity of nicotinic ACh-receptors of the sympathetic ganglion cell and skeletal muscle endplate, acting on a certain allosteric site but not the recognition site of ACh in the receptor-ionic channel complex.
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PMID:Substance P modulates the sensitivity of the nicotinic receptor in amphibian cholinergic transmission. 619 26

Strips of muscularis mucosae from the oesophagi of cat, dog and opossum have been studied to determine their responses to drugs to electrical field stimulation. All tissues were contracted by acetylcholine, histamine and, with the exception of strips of muscularis mucosae from the opossum proximal oesophagus, noradrenaline. The effects of acetylcholine and histamine were competitively antagonized by atropine (50 nM) and mepyramine (50 nM) and were abolished by atropine (1 microM) and mepyramine (1 microM) respectively. Contractile responses to noradrenaline were competitively antagonized by phentolamine (50 nM) but were converted to propranolol (50 nM)-sensitive relaxations by phentolamine (1 microM). Relaxations were abolished by propranolol (1 microM). Cholecystokinin octapeptide, gastrin 1 and vasoactive intestinal polypeptide were ineffective on any of the tissues examined. Substance P caused contractions in tissue from all three species. These effects were atropine and tetrodotoxin insensitive. All tissues gave atropine (50 nM)- and tetrodotoxin (100 nM)-sensitive contractions in response to electrical field stimulation. Contractions were not followed by relaxations and spontaneous mechanical activity was not suppressed between periods of stimulation. No evidence was obtained for the presence of non-adrenergic, non-cholinergic inhibitory innervation of the oesophageal muscularis mucosae in any species. During electrical field stimulation noradrenaline always reduced the amplitude of evoked contractions and, with the exception of tissue from proximal opossum oesophagus, increased resting tension. In opossum distal oesophageal muscularis mucosae, the effects of noradrenaline during electrical field stimulation were abolished by a 30 min pretreatment of the tissue with phentolamine (1 microM) and propranolol (1 microM). To Achieve this in all other tissues, it was also necessary to use yohimbine (1 microM). 7 In all tissues where noradrenaline caused a phentolamine (1 microM)-and propranolol (1 microM)- resistant depression of electrically evoked responses, clonidine produced a yohimbine (1 microM)- sensitive depression. 8 Evidence was obtained for the presence of excitatory alpha 1-and inhibitory alpha 2- and beta-adrenoceptors. Inter-species differences in their distribution are discussed.
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PMID:A pharmacological study of oesophageal muscularis mucosae from the cat, dog and American opossum (Didelphis virginiana). 620 83

The effects of substance P and the selective neurokinin-1 receptor antagonist (+/-)-CP-96,345 have been compared on in vitro spinal cord preparations from the rat and the gerbil. Substance P produced a concentration-dependent depolarization of motoneurons recorded from ventral roots of both species. The EC50 values (microM mean +/- S.E.M.) obtained in rat (0.95 + 1.0/-0.49) and gerbil (0.47 + 0.26/-0.17) preparations were comparable. The mean maximal depolarization (mV mean +/- S.E.M.) evoked in rat (2.07 + 0.26/-0.25) was approximately two-fold greater than that evoked in gerbil (1.21 + 0.15/-0.14) preparations. In the rat substance P had a biphasic effect (depression followed by potentiation) on the short latency probably monosynaptic reflex evoked by electrical stimulation of a dorsal root. In gerbil preparations substance P produced only potentiation of the monosynaptic reflex. The EC50 values (microM) mean +/- S.E.M.) for this potentiating action in rat (0.97 + 0.75/-0.43) and gerbil (0.46 + 3.6/-0.4) preparations were similar. This potentiation demonstrates a positive modulation of an endogenous excitatory probably glutamatergic transmission by substance P in the ventral horn of the spinal cord. The depressant phase observed in rat preparations may be related to the relative immaturity of myelination in rat ventral root fibres compared to the gerbil. The selective neurokinin-1 antagonist (+/-)-CP-96,345 was one hundred-fold less potent as an antagonist of substance P-induced depolarizations in the rat (pA2 4.69 +/- 0.18, n = 7) than in the gerbil (pA2 6.79 +/- 0.16, n = 5) spinal cord. This finding suggests that (+/-)-CP-96,345 may not act solely at the neurokinin-1 recognition site. In conclusion this study demonstrates that substance P modulates the monosynaptic reflex in the spinal cord presumably via activation of neurokinin-1 receptors.
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PMID:The modulation of the monosynaptic reflex by substance P in the hemisected spinal cord preparation of the rat and gerbil. 769 48

The pathogenesis of trigeminal neuralgia remains largely unknown. "Peripheral" as well as "central" causes have been suggested. To investigate the role of serotonergic, noradrenergic, dopaminergic, and peptidergic systems, we determined the concentrations of epinephrine, norepinephrine, and their breakdown product, vanillylmandelic acid, in the cerebrospinal fluid of 16 patients (55.3 +/- 8.3 years) with trigeminal neuralgia. As a marker for the dopaminergic system, we determined cerebrospinal fluid concentrations of dopamine and its metabolite, homovanillic acid. As a marker for the serotonergic system, we measured cerebrospinal fluid levels of the serotonin metabolite, 5-hydroxyindoleacetic acid. In addition, levels of the neuropeptides, substance P and somatostatin, were determined. The concentration of norepinephrine (P < 0.01) and its metabolite, vanillylmandelic acid, (P < 0.05) were significantly decreased in our patients. The level of the dopamine metabolite, homovanillic acid, was also significantly reduced (P < 0.01). Also significantly decreased was 5-hydroxyindoleacetic acid (P < 0.01). Substance P was significantly elevated (P < 0.05). Somatostatin was significantly decreased (P < 0.05). We hypothesize that the sum of complex neurochemical changes plays a role in the pathogenesis of trigeminal neuralgia. The elevated substance P could support the concept of a neurogenic inflammation in the trigeminovascular system, whereas changes in the monoaminergic transmitters and their metabolites seem to reflect a more central dysfunction possibly due to a longer duration of the disease and an accompanying depression.
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PMID:Cerebrospinal fluid neuropeptides and monoaminergic transmitters in patients with trigeminal neuralgia. 915 Jun 15

Receptors responsible for the tachykinin-induced depression of gamma-aminobutyric acid-A (GABAA) receptors in neurons of bullfrog dorsal root ganglia (DRG) were investigated by using whole-cell voltage-clamp techniques. Substance P (10 nM-1 microM) depressed the inward current produced by GABA (GABA current) in a concentration-dependent manner. Substance P did not change the reversal potential of the GABA current. Neurokinin A also depressed the GABA current with potency similar to those of substance P. [D-Arg1, D-Trp7,9, Leu11]substance P (spantide, 1 microM) shifted the concentration-inhibition curve of substance P to the right. Spantide (1 microM) increased the IC50 from 56 nM to 210 nM. Lineweaver-Burk plot, a reciprocal plot of the concentration-inhibition curve, showed that spantide did not change the maximum response (Vmax) to substance P but increased the apparent dissociation constant (Kd). CP99994 (1 microM), an neurokinin-1 (NK1) receptor antagonist, inhibited the substance P-induced depression of the GABA current. These results suggest that the tachykinin-induced depression of the GABAA receptor sensitivity is mediated by NK1 receptors in neurons of bullfrog DRG.
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PMID:Neurokinin-1 (NK1) receptors mediate tachykinin-induced depression of GABA current in bullfrog sensory neurons. 915 60

Although considered as an intestinal motor stimulant, substance P can inhibit intestinal peristalsis via stimulation of tachykinin NK1 receptors. Since NK1 receptors are present on enteric nitrergic neurones, the contribution of nitric oxide (NO) to the peristaltic motor inhibition caused by tachykinins was examined in luminally perfused segments of isolated guinea-pig ileum. Substance P (100 nM) and the NK1 receptor agonist substance P methyl ester (100 nM) increased the intraluminal pressure threshold at which peristaltic contractions were elicited. This inhibitory influence on peristalsis was prevented by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (300 microM) in an enantiomer-selective manner. It is concluded that the substance P/NK1 receptor-mediated depression of intestinal peristalsis involves inhibitory motor pathways utilizing NO as a transmitter.
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PMID:Involvement of nitric oxide in the substance P-induced inhibition of intestinal peristalsis. 937 19

A role for serotonin in migraine has been supported by changes in circulating levels of serotonin and its metabolites during the phases of a migraine attack, along with the ability of serotonin-releasing agents to induce migraine-like symptoms. The development of serotonin receptor agonists with efficacy in the clinic for the alleviation of migraine pain further implicates serotonin as a key molecule in migraine. Several theories regarding the etiology of migraine have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilation during an attack was related to migraine pain; a theory supported when vasoconstrictors such as sumatriptan alleviated migraine pain. The neurological theory of migraine proposed that migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of migraine. The neurogenic dural inflammation theory of migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substance P, calcitonin gene related peptide and nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of migraine have been utilized to study the physiology of migraine and develop new pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural inflammation quantified by the resulting extravasation of proteins. Pharmacological agents such as meta-chlorophenylpiperazine (mCPP) and nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce migraine attacks in individuals with a history of migraine. In addition, Fos, a protein produced by activation of the c-fos gene, has been measured as an index of migraine-like pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for serotonin in migraine is further supported by the efficacy of serotonin receptor ligands. Sumatriptan is an agonist at 5-HT1D and 5-HT1B receptor subtypes, and effective in treating migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of migraine, without the side effects associated with the present 5-HT1D and 5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of migraine, supporting use of selective 5-HT2B receptor antagonists in migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the therapy of migraine headache.
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PMID:Serotonin in migraine: theories, animal models and emerging therapies. 994 63

Paired intracellular recordings have been used to examine the activity-dependent plasticity and neuromodulator-induced metaplasticity of synaptic inputs from identified inhibitory and excitatory interneurons in the lamprey spinal cord. Trains of spikes at 5-20 Hz were used to mimic the frequency of spiking that occurs in network interneurons during NMDA or brainstem-evoked locomotor activity. Inputs from inhibitory and excitatory interneurons exhibited similar activity-dependent changes, with synaptic depression developing during the spike train. The level of depression reached was greater with lower stimulation frequencies. Significant activity-dependent depression of inputs from excitatory interneurons and inhibitory crossed caudal interneurons, which are central elements in the patterning of network activity, usually developed between the fifth and tenth spikes in the train. Because these interneurons typically fire bursts of up to five spikes during locomotor activity, this activity-dependent plasticity will presumably not contribute to the patterning of network activity. However, in the presence of the neuromodulators substance P and 5-HT, significant activity-dependent metaplasticity of these inputs developed over the first five spikes in the train. Substance P induced significant activity-dependent depression of inhibitory but potentiation of excitatory interneuron inputs, whereas 5-HT induced significant activity-dependent potentiation of both inhibitory and excitatory interneuron inputs. Because these metaplastic effects are consistent with the substance P and 5-HT-induced modulation of the network output, activity-dependent metaplasticity could be a potential mechanism underlying the coordination and modulation of rhythmic network activity.
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PMID:Activity-dependent metaplasticity of inhibitory and excitatory synaptic transmission in the lamprey spinal cord locomotor network. 1002 51

A marked depression of swallowing reflex has been found in patients with aspiration pneumonia. We have examined the effects of Banxia Houpo Tang (BHT, Hange Koboku-To in Japanese), on swallowing reflex among the elderly. Thirty-two patients, mean age 74.2 +/- 1.7 years who had at least one episode of aspiration pneumonia, were divided into two groups. Twenty patients took BHT extracts of 7.5 g per day for four weeks, and the other 12 patients took a placebo. The swallowing reflex was measured by a bolus injection of 1 ml of distilled water into the pharynx through a nasal catheter. The reflex was evaluated by the latency time of response, which was the time from the injection to the onset of swallowing. The latency of response decreased significantly from 11.6 +/- 3.0 sec to 2.6 +/- 0.4 sec in the group treated with BHT (p < 0.01), while in the other group with placebo it was from 11.0 +/- 4.0 to 10.8 +/- 3.6 (p > 0.5). Depletion of substance P in the pharynx causes impairments of the swallowing reflex. Substance P in the saliva of treated patients increased from 9.2 +/- 2.5 fmol/ml to 15.0 +/- 2.2 fmol/ml after BHT treatment (p < 0.01), while levels were 8.0 +/- 4.0 fmol/ml before and 7.1 +/- 3.1 fmol/ml after among the placebo group (no significant difference). We suggest that BHT improves the impaired swallowing reflex and may help to prevent aspiration pneumonia in the elderly.
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PMID:The traditional Chinese medicine banxia houpo tang improves swallowing reflex. 1037 48

The field of neuropeptides has been expanding very rapidly in recent years. Apart from understanding their physiology and elucidating their functional role as putative neurotransmitters, research has focused on producing drugs that may treat a variety of illnesses in a novel way. Substance P antagonists occupy a central role in this area of intensive scientific activity. Substance P (SP), an undecapeptide, is abundant both in the periphery and in the CNS, where it is usually co-localised with one of the classical neurotransmitters, most commonly serotonin (5-HT). A role for SP is proposed in the regulation of pain, asthma, psoriasis, inflammatory bowel disease and, in the CNS, emesis, migraine, schizophrenia, depression and anxiety. A recently published positive study of MK 869, in depression, a novel SP antagonist has generated excitement amongst psychopharmacologists. It is the first time that a drug, not directly related to monoamine transmitters, has showed efficacy in depression. Although MK 869 has been suspended from further development, a host of other compounds, with similar action and better pharmacological profile, are currently under development. In this review, the pharmacology of central SP and its receptors are discussed, together with the exploration of the prospects and implications for future treatments of depression.
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PMID:Substance P antagonists: novel agents in the treatment of depression. 1106 Jul 83

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