Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intravenous administration of the NK1 receptor antagonist L-733,060 to gerbils 3 h before intraplantar injection of formalin caused a dose-dependent and complete inhibition of the late, but not early, phase nociceptive response (paw licking). The ID50 for L-733,060 (0.17 mg/kg) revealed a greater than 50-fold separation in potency over its less active enantiomer L-733,061 (ID50 > or = 10 mg/kg). In contrast, the non-brain penetrant quaternary ketone NK1 receptor antagonist, L-743,310 (3 mg/kg), did not attenuate the response to formalin, indicating that the antinociceptive effect of blockade of NK1 receptors by L-733,060 in this assay is centrally-mediated. These findings add to the preclinical evidence that NK1 receptor antagonists may be of therapeutic use as centrally-acting analgesics.
Pain 1996 Sep
PMID:Enantioselective inhibition of the formalin paw late phase by the NK1 receptor antagonist L-733,060 in gerbils. 889 47

Immunohistochemical staining for the substance P (neurokinin INK1) receptor labels 32% of the unmyelinated axons in the glabrous skin of the rat hindpaw. This is the first demonstration of substance P (SP) receptors associated with the membranes of primary afferent fibers. Injection of SP into the subcutaneous tissue of the third hind toe results in behavioral changes interpreted as mechanical hyperalgesia and mechanical allodynia. These nocifensive behaviors can be blocked by the NK1 antagonist CP99,994-1. The presence of peripheral axons immunolabelled for NK1 receptors and the demonstration that exogenous peripheral SP causes nocifensive behaviors would seem to indicate that SP can have a direct effect on sensory afferents with activation of these receptors resulting in fine afferent firing and thus the pain-related behaviors. Additionally, the presence of round, clear vesicles in some of the SP receptor-labelled axons suggests the presence of autoreceptors since it is known that many primary sensory afferents contain SP.
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PMID:Localization and activation of substance P receptors in unmyelinated axons of rat glabrous skin. 889 15

Tachykinins, colocalized with calcitonin gene-related peptides (CGRP) in sensory afferents, are involved in viscerosensitive responses. We investigated the role of tachykinins and CGRP in both nociceptive and visceromotor responses to inflammation. Visceral pain was assessed by abdominal muscle contractions. Gastric emptying was evaluated after gavage with reconstituted milk containing 51Cr-labeled sodium chromate. Acetic acid or 9% NaCl was injected intraperitoneally before the meal. RP-67580, SR-48968, human CGRP [hCGRP-(8-37)], or their vehicles were injected before acetic acid or saline. RP-67580, SR-48968, or their vehicles were injected before CGRP and the meal. GR-73632 or GR-76349 was injected before the meal. Acetic acids inhibited gastric emptying and increased the number of abdominal contractions. RP-67580 reduced the inhibition of gastric emptying without affecting the abdominal response. SR-48968 only reduced the acetic acid-induced increase of abdominal contractions. hCGRP-(8-37) reduced both responses induced by acetic acid. CGRP mimicked the effects of acetic acid. RP-67580 abolished CGRP-induced gastric emptying inhibition, whereas SR-48968 only diminished visceral pain. GR-73632 reduced gastric emptying, and GR-64349 increased abdominal response. In inflammation, neurokinin receptors (NK1 and NK2) mediate the gastric emptying inhibition and visceral pain, respectively. These responses involve a release of CGRP.
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PMID:Tachykininergic mediation of viscerosensitive responses to acute inflammation in rats: role of CGRP. 903 87

The preprotachykinin-A gene-derived peptides substance P and neurokinin (NK) A are expressed in distinct neural pathways of the mammalian gut. When released from intrinsic enteric or extrinsic primary afferent neurons, tachykinins have the potential to influence both nerve and muscle by way of interaction with three different types of tachykinin receptor, termed NK1, NK2 and NK3 receptors. Most prominent among the effects of tachykinins is their excitatory action on gastrointestinal motor activity, which is seen in virtually all regions and layers of the mammalian gut. This action depends not only on a direct activation of the muscle through NK1 and/or NK2 receptors, but also on stimulation of excitatory enteric motor pathways through NK3 and/or NK1 receptors. In addition, tachykinins can inhibit motor activity by stimulating either inhibitory neuronal pathways or interrupting excitatory relays. A synopsis of the available data indicates that endogenous substance P and NKA interact with other enteric transmitters in the physiological control of gastrointestinal motor activity. Derangement of the regulatory roles of tachykinins may be a factor in the gastrointestinal dysmotility associated with infection, inflammation, stress and pain. In a therapeutic perspective, it would seem conceivable, therefore, that tachykinin agonists and antagonists are adjuncts to the treatment of motor disorders that involve pathological disturbances of the gastrointestinal tachykinin system.
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PMID:Tachykinins in the gut. Part I. Expression, release and motor function. 917 55

The mammalian tachykinins (substance P, neurokinin A, and neurokinin B) are widely distributed throughout the central and peripheral nervous systems, where they act as neurotransmitters or neuromodulators. Historically, the tachykinins have been implicated in a wide variety of biological actions such as pain transmission, neurogenic inflammation, smooth muscle contraction, vasodilation, secretion, and activation of the immune system. Their effects are mediated via specific G-protein-coupled receptors (NK1, NK2, and NK3 receptors). The development of nonpeptide receptor antagonists revealed species differences in neurokinin-receptor pharmacology, and the recent cloning of human neurokinin receptors has led to development of compounds with optimized affinity for the human target receptor. The neurokinin-receptor antagonists have been used in preclinical experiments to confirm the physiological roles of the tachykinins. Importantly, it is now recognised that these agents can inhibit the actions of tachykinins released from peripheral nerves, and for the NK1-receptor antagonists (the most widely studied class of neurokinin-receptor antagonists) central sites of action have also been demonstrated. These studies support the development of neurokinin-receptor antagonists as potentially exploitable drug therapies in humans, particularly in the treatment of pain and emesis.
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PMID:Neurokinin-receptor antagonists: pharmacological tools and therapeutic drugs. 927 38

The intradermal (i.d.) injection of NK1 receptor antagonists GR 82334 and FK 888 (1-50 pmol/paw), in association with formalin, produced graded inhibition of the early but not the late phase of the formalin test. The NK2, SR 48968 and NK3 SR 142801 receptor antagonists (1-50 pmol/paw) were effective in inhibiting both phases of the formalin model. Co-injection of NK1, (FK 888, GR 82334), NK2 (SR 48968) or NK3 (SR 142801) receptor antagonists with capsaicin dose-dependently attenuated capsaicin-induced licking. In addition, all antagonists were more efficacious when compared with response in the formalin test. The antinociception caused by i.d. injection of the NK3 receptor antagonist SR 142801 against both phases of the formalin test, but not that of NK1 and NK2 receptor antagonists, was significantly reversed by intraperitoneal (i.p.) injection of naloxone (5 mg/kg). Intracerebroventricular (i.c.v.) injection of NK1, NK2 or NK3 receptor antagonists (15-500 pmol/site), all produced significant and dose-dependent inhibition of both phases of the formalin and capsaicin tests. With the exception of the response of SR 48968, which was equipotent in both models of nociception, FK 888, GR 82334 and SR 142801 were about 2-25-fold less potent at the ID50 level against the capsaicin-induced pain. The antinociception caused by i.c.v. injection of NK1, NK2 or NK3 receptor antagonists was reversed by i.p. injection of naloxone (5 mg/kg). These results indicate that tachykinin receptor antagonists, acting through NK1, NK2 and NK3 receptors, produce powerful antinociception when injected i.d. or by i.c.v. route against both formalin- and capsaicin-induced licking, being more efficacious against the latter model of nociception. The action of NK3 receptor antagonist given i.d. was mediated through an opioid mechanism sensitive to naloxone. However, when injected i.c.v., the antinociception caused by NK1, NK2 or NK3 receptor antagonists was largely reversed by naloxone when assessed in the formalin test, suggesting a distinct mechanism of action.
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PMID:Further evidence for the involvement of tachykinin receptor subtypes in formalin and capsaicin models of pain in mice. 930 27

Substance P (SP) is a peptide found in the sensory nervous system which has multiple biologic effects including stimulation of muscle contraction, pain nociception, immune cell functions, plasma extravasation and a constellation of inflammatory effects. Here we investigate the role of SP in several animals models of bladder inflammation. Using the female Lewis rat, inflammation was induced using either xylene, lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (polyIC). Inflammation occurred rapidly (4 h) and was maintained in each model for at least 7 days. Each of these protocols decreased the bladder content of immunoreactive SP by approximately 50%, suggesting enhanced release. There was no change in the urinary frequency of these animals over 3 weeks, suggesting that urinary frequency changes are not mediated by acute inflammation. We also found that the SP receptor (NK1) antagonist, (-)CP96345, was unable to block the inflammation produced by polyIC, suggesting that SP is not an obligatory mediator of immune cell stimulation in this model.
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PMID:Role of substance P in several models of bladder inflammation. 944 48

Trigeminal stimulation of C-fibers increased c-fos expression within the trigeminal nucleus caudalis (NtV) and thalamic neuronal activity which both reflect the transmission of a nociceptive message. We examined the effects on both these phenomena of the selective NK1 and NK2 receptor antagonists, SR140333 and SR48968. SR140333 (0.3, 1 and 3 micrograms/kg intravenously [i.v.]) dose-dependently, reversibly and stereoselectively antagonized the increase of contralateral thalamic activity. This compound, when given i.v. (30 micrograms/kg) or orally (10 mg/kg), also reduced the number of Fos-like immunoreactive cells particularly at the medial and caudal level of the NtV. In contrast, SR48968 did not exert any antagonistic effect either on thalamic activity or on Fos-like immunoreactivity. The data strongly suggest a preferential involvement of NK1 vs NK2 receptors in nociceptive transmission following trigeminal ganglion stimulation. Taken together, our results indicate that SR140333 could provide a potent drug for the relief of pain occurring under excessive activity of sensory trigeminal fibers.
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PMID:Effects of SR140333, a selective non-peptide NK1 receptor antagonist, on trigemino-thalamic nociceptive pathways in the rat. 952 90

The tachykinin NK1 receptor is widely distributed in both the central and peripheral nervous system. In the CNS, NK1 receptors have been implicated in various behavioural responses and in regulating neuronal survival and degeneration. Moreover, central NK1 receptors regulate cardiovascular and respiratory function and are involved in activating the emetic reflex. At the spinal cord level, NK1 receptors are activated during the synaptic transmission, especially in response to noxious stimuli applied at the receptive field of primary afferent neurons. Both neurophysiological and behavioural evidences support a role of spinal NK1 receptors in pain transmission. Spinal NK1 receptors also modulate autonomic reflexes, including the micturition reflex. In the peripheral nervous system, tachykinin NK1 receptors are widely expressed in the respiratory, genitourinary and gastrointestinal tracts and are also expressed by several types of inflammatory and immune cells. In the cardiovascular system, NK1 receptors mediate endothelium-dependent vasodilation and plasma protein extravasation. At respiratory level, NK1 receptors mediate neurogenic inflammation which is especially evident upon exposure of the airways to irritants. In the carotid body, NK1 receptors mediate the ventilatory response to hypoxia. In the gastrointestinal system, NK1 receptors mediate smooth muscle contraction, regulate water and ion secretion and mediate neuro-neuronal communication. In the genitourinary tract, NK1 receptors are widely distributed in the renal pelvis, ureter, urinary bladder and urethra and mediate smooth muscle contraction and inflammation in response to noxious stimuli. Based on the knowledge of distribution and pathophysiological roles of NK1 receptors, it has been anticipated that NK1 receptor antagonists may have several therapeutic applications at central and peripheral level. At central level, it is speculated that NK1 receptor antagonists could be used to produce analgesia, as antiemetics and for treatment of certain forms of urinary incontinence due to detrusor hyperreflexia. In the peripheral nervous system, tachykinin NK1 receptor antagonists could be used in several inflammatory diseases including arthritis, inflammatory bowel diseases and cystitis. Several potent tachykinin NK1 receptor antagonists are now under evaluation in the clinical setting, and more information on their usefulness in treatment of human diseases will be available in the next few years.
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PMID:The tachykinin NK1 receptor. Part II: Distribution and pathophysiological roles. 957 43

Distension of the rat intestine causes a cardiovascular response which is indicative of nociception. Since tachykinins are involved in nociception, we tested the effect of neurokinin receptor antagonists against the distension-induced response. The jejunal distension-induced depressor responses were inhibited in a dose-dependent fashion by CP 99,994 (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine, tachykinin NK1 receptor antagonist, ED50 = 0.8 mg/kg) and SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichloropheny l)butyl]benzamide, tachykinin NK2 receptor antagonist, ED50 = 0.7 mg/kg). SR 142801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)prop yl)-4-phenylpiperidin-4-yl)-N-methylacetamide, tachykinin NK3 receptor antagonist, 0.3-10 mg/kg) did not significantly affect the depressor responses to jejunal distension. In addition, CP 99,994 (3 mg/kg) and SR 48968 (3 and 10 mg/kg) reduced sensitivity to distension as revealed by a 2.7-fold (CP 99.994, 3 mg/kg), 2.6-fold (SR 48968, 3 mg/kg) and 4.7-fold (SR 48968, 10 mg/kg) increase in the threshold pressure. Intestinal compliance was not affected by the antagonists. In conclusion, these results suggest that tachykinin NK1 and NK2 but not NK3 receptors are possibly involved in the rat jejunal distension pain response.
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PMID:Effects of tachykinin receptor antagonists on the rat jejunal distension pain response. 959 22


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