Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that intrathecal NSAIDs can produce a significant, dose-dependent reduction in the second phase of the formalin response and block thermal hyperalgesia induced by spinally injected N-methyl-D-aspartate and substance P. These observations support the body of literature that indicate that sustained small fiber input yields a hyperalgesia through activation of spinal NMDA and NK1 receptors and that in turn a portion of this action is mediated by the spinal release of cyclooxygenase products.
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PMID:Spinal actions of NSAIDS in blocking spinally mediated hyperalgesia: the role of cyclooxygenase products. 831 44

A large body of recent evidence suggests that a number of inhibitory and excitatory neuropeptides and amino acids may participate in the episodic secretion of hypothalamic LHRH and pituitary LH in castrated rats. However, the precise functional relationships among these messenger molecules in the control of LH secretion remain to be ascertained. The aim of this study was to test the hypothesis that inhibition of LH release by an opioid [beta-endorphin (beta END)], cytokine [interleukin-1 beta (IL-1 beta)], or tachykinin [neuropeptide-K (NPK)] is a result of diminished excitatory amino acid (EAA) signaling. Adult male rats were castrated and received an intracerebroventricular cannula in the third ventricle for administration of beta END (10 micrograms/rat), NPK (2.5 nmol/rat), or IL-1 beta (100 ng/rat) 2 weeks postcastration. One day before the experiments, rats received an intraatrial cannula for frequent blood sampling and for iv injection of the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 5 mg/kg) at 30-min intervals. Blood samples for LH measurements were withdrawn immediately before and 10 min after each NMDA injection. The results show that intracerebroventricular beta END, IL-1 beta, or NPK inhibited LH release. Multiple injections of NMDA did not alter the existing pattern of LH secretion in castrated control rats. However, similar NMDA injections completely prevented the decrease in LH release by beta END, IL-1 beta, or NPK. Plasma LH levels in these rats remained within the range seen in untreated control rats throughout the 120-min duration of the experiment, and NMDA injections at 30-min intervals evoked pulses of LH that resembled those seen normally in castrated rats. The blockade of the inhibitory effects of the three peptides by NMDA and previous knowledge of hypothalamic sites of NMDA action suggest that EAA systems may represent a common pathway down-stream in the hypothalamic LHRH-regulating circuitry to mediate diminution of LH release by inhibitory peptides. Further, their inhibitory influence may be exerted either directly at the level of LHRH neurons and/or by diminution in EAA efflux, leading to suppression of LHRH and LH release.
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PMID:Evidence that luteinizing hormone suppression in response to inhibitory neuropeptides, beta-endorphin, interleukin-1 beta, and neuropeptide-K, may involve excitatory amino acids. 831 64

Pre-emptive analgesia is based on the idea that analgesia initiated before a nociceptive event will be more effective than analgesia commenced afterwards, and that its effects will outlast the pharmacological duration of action of the analgesic used. The idea of pre-emptive analgesia is based upon experimental neurophysiological work demonstrating that afferent nociceptive impulses result in alterations of central nervous system function. These changes, most easily elicited by C-fibre afferents, particularly affect the spinal dorsal horn. Termed central sensitisation, they are reflected by reduced pain thresholds (allodynia), increased responses to pain (hyperalgesia), after-discharging or spontaneous activity of dorsal horn neurons (wind-up), and extension of hypersensitivity to unaffected tissues (secondary hyperalgesia). Their biochemical basis is now being unravelled, with excitatory amino acid (e.g. NMDA) and neuropeptide (e.g. substance P) neurotransmitters playing prominent roles. Blockade of these receptors has recently been shown to depress the central sensitisation associated with nociception. Ketamine, a non-competitive NMDA receptor blocker, for example, has been shown modulate postoperative pain in a positive way. Although the existence of central sensitisation is now being clinically demonstrated, studies of pre-emptive analgesia in the surgical context have not revealed clinically significant effects. This is probably because surgical nociception is much longer-lasting, multimodal and intense than its experimental counterparts. Clinical studies have so far only used short-term analgesia. To permit extrapolation from the experimental to the clinical situation, pre-emption in the surgical context must correspond adequately to the duration and extent of the nociception involved. Studies of pre-emptive analgesia in a clinically relevant form, i.e. where nociception and analgesia are correctly matched, are called for.
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PMID:[Pre-emptive analgesia]. 859 63

This review summarises our current understanding of the neurotransmitters involved in the generation, transmission and modulation of respiratory rhythm. The principal neurotransmitters involved in generating and transmitting respiratory rhythm include glutamate, GABA, and glycine. Glutamate acts primarily at non-NMDA receptors within the networks to generate respiratory rhythm in neonatal in vitro preparations, but it may also engage NMDA receptors in mature intact animals. Glutamate may likewise act as presynaptic AP-4 metabotropic receptors to fine tune its own release in the transmission of respiratory rhythm to the phrenic motoneurones. The role of other metabotropic receptors in rhythmogenesis is not known. GABA (primarily by acting at GABAA receptors), as well as glycine, transmit phasic waves of inhibition within the primary respiratory network. Neuroactive agents synthesized outside the primary network may shape the final expression of the basic rhythm. The most studied inputs originate in the pons and from the slowly adapting pulmonary stretch receptors (SAR). Both of these inputs contribute to the transition from inspiration to expiration. Pontine mechanisms rely on excitatory amino acid activation of NMDA receptors, while SAR pathways utilize non-NMDA receptors. Serotonin has also been implicated in regulating respiratory rhythm, possibly via serotonergic projections originating in the raphe nuclei. The amine has diverse effects on respiratory neuronal activity; the most consistent effect appears to be an augmentation of phrenic motoneuronal at the level of the spinal cord. Substance P regulates respiratory activity by acting in the CNS and on peripheral sensory receptors. Centrally, substance P largely augments respiration, by increasing respiratory rhythm in neonatal in vitro preparations and also by increasing tidal volume in the intact animal. Substance P is also released by carotid chemoreceptor afferents during hypoxia. Opioids are well known to decrease respiration; the central mechanism involves the suppression of baseline inspiratory neuronal activity and possibly the blunting of glutamate-evoked increases in inspiration drive.
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PMID:Neurotransmitters in the CNS control of breathing. 860 95

The present study examined the effects of chronic treatment with dizocilpine maleate (0.2 mg/kg i.p., twice a day for 8 days) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic neurons on substance P and enkephalin expression in the rat striatum. This was done by means of quantitative in situ hybridization histochemistry and immunocytochemistry. As reported previously, the unilateral dopaminergic lesion resulted in marked decreases in substance P mRNA expression and immunoreactivity in the ipsilateral striatum while enkephalin mRNA expression and Met-enkephalin immunoreactivity were considerably increased in this structure. Blockade of NMDA receptors by chronic dizocilpine maleate treatment alone resulted in decreased levels of striatal substance P mRNA without significant change in substance P immunoreactivity versus controls. Enkephalin mRNA levels were also decreased in the striatum, matched by parallel reductions in Met-enkephalin immunoreactivity. These observations indicate that NMDA receptor activity may exert tonic excitatory effects on substance P and enkephalin expression in the striatum. The same chronic treatment with dizocilpine maleate started 12 days after the 6-hydroxydopamine injection suppressed the lesion-induced up-regulation of enkephalin expression without significantly affecting the down-regulation of substance P expression. These data provide evidence that NMDA receptor-mediated mechanisms contribute to the alteration of striatal enkephalin expression associated with dopaminergic depletion in hemiparkinsonian rat models.
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PMID:Chronic dizocilpine maleate (MK-801) treatment suppresses the effects of nigrostriatal dopamine deafferentation on enkephalin but not on substance P expression in the rat striatum. 874 39

The distribution of glutamate receptors in the developing striatum of the rat was studied using antibodies specific to AMPA and NMDA subtypes. Immunocytochemistry revealed a greater density of GluR1, GluR2/3, NMDAR1, and NMDAR2A/2B receptors in patches that matched the patches of substance P-immunoreactive neurons and dopaminergic terminals. GluR1-immunoreactive patches were the most distinctive and were present already at embryonic day 19.
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PMID:Glutamate receptor subtypes localize to patches in the developing striatum. 883 85

A variety of pharmacologic approaches to the management of pain due to nerve damage have been tried, with mixed results. Sympathetically maintained pain responds most commonly to sympathetic nerve blocks. Oral nifedipine may be a useful adjunct. Many-but not all-neuropathic pain patients experience relief from low-dose tricyclic antidepressants. When those drugs are not sufficient, the addition of an anticonvulsant, systemic local anesthetic, or both, to the antidepressant may be useful. Neuropathic pain with a major cutaneous component may respond well to topical therapy with the Substance P depletor capsaicin to reduce elevated prostaglandin levels. Topical therapy is most commonly used as an adjunct to systemic drugs. There is now good evidence that early treatment of acute herpes neuralgia with famciclovir may be effective in reducing postherpetic neuralgia. The role of opioids in chronic nerve pain is unclear. Most patients do not respond to these drugs, and should not receive them. Many patients with chronic neuropathic or sympathetically maintained pain need detoxification from opioids, sedative-hypnotics, and muscle relaxants. Some patients cannot carry out normal activities of daily living without opioids, however, and function well while taking low-dose, regularly scheduled opioids. The prognosis for successfully managing neuropathic and sympathetically maintained pain is greatly improved if appropriate therapy is initiated early in the course of the pain. When patients do not respond adequately to initial drug therapy, referral to an interdisciplinary pain management program for evaluation may be in order. Many neuropathic and SMP patients have complex pain syndromes which are most effectively managed through a coordinated, interdisciplinary approach. Careful attention to medical, pharmacologic, psychologic, and physical factors are the hallmarks of this type of treatment. The drugs now available provide marked relief to the majority of patients when therapy includes careful attention to the various dimensions of the pain syndrome. Although consistently effective drug therapy for all neuropathic and sympathetically maintained pain is not yet available, the probability of new NMDA antagonists being introduced in the next few years offers promise.
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PMID:Analgesic drugs for neuropathic and sympathetically maintained pain. 885 42

Studies in which glutamate (GLU) neurotransmission has been reduced at striatal synapses have shown that GLU influences the biosynthesis of certain peptide cotransmitters by striatal neurons. The present experiment was designed to test the effects of direct activation of the NMDA or AMPA types of GLU receptor on the levels of two mRNAs that encode the peptide cotransmitters met5-enkephalin (ME) and substance P (SP). In situ hybridization histochemistry of forebrain tissue sections from rats 8 h after a single intracerebroventricular infusion of NMDA or AMPA revealed a significant and dose-dependent elevation (to a maximum of almost 50%) of striatal ME mRNA when compared to vehicle-injected controls. SP mRNA was not significantly affected. NMDA was more effective than AMPA over the dose range used. Pretreatment with a potent and highly specific AMPA antagonist (NBQX) predictably blocked the AMPA-mediated elevation, and was only slightly effective against the NMDA-induced response. In striking contrast, pretreatment with a potent and highly selective NMDA antagonist (CGP37849) fully opposed both the NMDA- and the AMPA-mediated elevation of ME mRNA. These data further implicate the NMDA receptor in the regulation of peptide cotransmitter gene transcription. They suggest also that the AMPA receptor may play an indirect, synergistic role in the genetic responses of striatal neurons to GLU transmission.
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PMID:N-methyl-D-aspartate acutely increases proenkephalin mRNA in the rat striatum. 886 64

The intrathecal (i.t.) injection of capsaicin (0.1 nmol/mouse) through a lumbar puncture elicited scratching, biting and licking responses. Pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (320 nmol), by i.t. injection, resulted in a significant inhibition of the behavioural response produced by i.t. capsaicin (0.1 nmol/mouse). Similar behavioural responses were induced by i.t. injections of NMDA (0.4 nmol), kainate (0.05 nmol) or AMPA (0.05 nmol), which were all inhibited by co-administration of L-NAME (20-80 nmol). L-Arginine (600 mg/kg, i.p.) but not D-arginine (600 mg/kg, i.p.) reversed the inhibitory effect of L-NAME on capsaicin-, NMDA-, kainate- and AMPA-induced behavioural response. Scratching, biting and licking responses induced by tachykinin receptor agonists, substance P, [Sar9,Met(O2)11]substance P, neurokinin A and neurokinin B were not affected by co-administration of L-NAME (40 and 80 nmol). These results suggest that spinal nitric oxide may play a significant role in mechanisms of the behavioural response to capsaicin, probably through the release of glutamate, but not tachykinins.
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PMID:Involvement of nitric oxide in spinally mediated capsaicin- and glutamate-induced behavioural responses in the mouse. 888 86

That substance P (SP) contributes in some way to spinal nociceptive processing has been known for many years. However, the contribution of SP and NK-1 receptors to the generation and maintenance of inflammatory hyperalgesia or persistent chemical hyperalgesia is not clear. The purpose of this study was to test the hypothesis that SP contributes to the generation but not maintenance of hyperalgesia using two models of inflammatory pain: carrageenan, which allows for testing of acute noxious thermal and mechanical stimuli, and formalin, a model of spontaneous pain. Intrathecal pretreatment with the NK-1 receptor antagonist CP-96,345 (100, 50, 25 nmol) dose-dependently attenuated the thermal (46%, 27% and 16%, respectively) and mechanical (66%, 37% and 3%, respectively) hyperalgesia produced by 2 mg carrageenan, but not 6 mg carrageenan, 3 h after the induction of inflammation. The attenuation was still apparent at 5 h for the greatest dose, but at 7 h the magnitude of hyperalgesia was equal to rats pretreated with saline. Posttreatment with 100 nmol CP-96,345 following the establishment of hyperalgesia had no effect. Intrathecal pretreatment with 125 nmol CP-96,345 prior to formalin (1% or 5%) injection into the hindpaw produced an overall 29% or 23% attenuation, respectively, of the nociceptive behavior during the 1-h observation period. For both 1% and 5% formalin injections, the phase 2 response, but not the phase 1 response, was significantly lower than that from rats pretreated both saline. Pretreatment with 100 or 125 nmol of the inactive enantiomer, CP-96,344, was no different than pretreatment with saline. A dose of 250 nmol CP-96,345 produced voluntary paralysis yet the flexion reflex to noxious pinch remained. These results support the hypothesis that SP contributes to the generation of inflammatory hyperalgesia but once established, the contribution of SP to maintaining the state of hyperalgesia is reduced. The interaction of SP, NK-1 receptors and spinal NMDA receptors in relation to inflammatory pain is discussed.
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PMID:The spinal contribution of substance P to the generation and maintenance of inflammatory hyperalgesia in the rat. 889 43


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