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)

Using receptor binding and autoradiographic techniques, changes in Bolton-Hunter labeled 125I-substance P (125I-BH-SP) binding were determined in laminae I/II, V and X of rat lumbar spinal cord after chronic constriction injury (CCI) of the sciatic nerve. When compared to the sham-operated side of the control group, SP binding significantly increased ipsilateral to the CCI in laminae I/II at 5, 10 and 20 days after injury and in lamina V at 5 days after injury. Scatchard analysis was performed on the 125I-BH-SP binding to the NK1 receptor in laminae I/II of rats 5 days after generation of the CCI. A significant decrease in the Kd of 125I-BH-SP binding was observed in laminae I/II ipsilateral to CCI when compared with the control side (ipsilateral to sham surgery). There was no significant change in the Bmax in laminae I/II ipsilateral to CCI. The changes in 125I-BH-SP binding in the rat spinal cord that occurred after CCI were found in areas of the spinal cord that receive terminations of nociceptive primary afferent fibers. The increased affinity of the NK1 binding site that we report could result in an increase in SP receptor activation in laminae I/II. Such central changes in SP binding may contribute to the neuropathic pain syndrome observed in rats with the CCI.
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PMID:Autoradiographic analysis of 125I-substance P binding in rat spinal cord following chronic constriction injury of the sciatic nerve. 128 46

The non-peptide NK1 receptor antagonist, (+/-)-CP-96,345, has been evaluated for antinociceptive activity in two well-characterized inflammatory pain models in the rat. (+/-)-CP-96,345 abolished carrageenin-induced mechanical hyperalgesia, significantly reduced carrageenin-induced paw oedema and attenuated the second phase of the formalin response. The results suggest that NK1 receptor activation occurs during the induction of inflammatory pain states in the rat.
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PMID:The non-peptide NK1 receptor antagonist, (+/-)-CP-96,345, produces antinociceptive and anti-oedema effects in the rat. 132 Sep 77

The non-peptide NK1 receptor antagonist, CP-96,345, and its 2R,3R enantiomer CP-96,344, which is not an NK1 receptor antagonist (IC50 > 10 microM), were evaluated for antinociceptive and anti-inflammatory activities in several classical models of pain and inflammation in the rat. Both CP-96,345 and CP-96,344 reduced carrageenin-induced paw oedema and hyperalgesia, and attenuated the second phase of formalin-induced paw licking with equal potency. These results indicate that NK1 antagonism is not responsible for the activity of (+/-)-CP-96,345 in the above animal models.
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PMID:Non-specific activity of (+/-)-CP-96,345 in models of pain and inflammation. 133 Jan 70

CP-96,345, a potent non-peptide antagonist of the substance P (SP) receptor, inhibited SP-, neurokinin A (NKA)- and neurokinin B-induced plasma extravasation in guinea pig dorsal skin. The inhibition was specific for the three tachykinins; CP-96,345 was not active against plasma leakage caused by histamine, bradykinin, platelet-activating factor or leukotriene D4. CP-96,345 inhibited capsaicin-induced plasma extravasation in the ureter, an inflammatory response caused by neuropeptides released from afferent C-fibers. Thus, the NK1 receptor appears to play a major role in vascular permeability increases induced by exogenous and endogenous tachykinins. In contrast, CP-96,345 was inactive against SP- and NKA-induced contraction of guinea pig ureter, suggesting that the smooth muscle contraction is not NK1-mediated. CP-96,345 exhibited analgesic activity in acetic acid-induced abdominal stretching in mice, indicating for the first time that SP plays a critical role in this model. The results of these studies support a pathophysiological role of SP and NK1 receptor under acute neurogenic inflammatory conditions and in pain.
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PMID:Antiinflammatory and analgesic activity of a non-peptide substance P receptor antagonist. 133 May 89

We describe here the pharmacological properties of RP 67580 [(3aR,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] perhydroisoindol-4-one], a nonpeptide antagonist of substance P (SP). In vitro, the compound was found to inhibit in a competitive manner (Ki = 4.16 +/- 0.59 nM) [3H]SP binding to neurokinin receptors type 1 (NK1 receptors) in rat brain membranes. Contractions induced by SP and septide (a selective NK1 agonist) in guinea pig ileum were competitively inhibited by RP 67580 (pA2 = 7.16 and 7.59, respectively). Moreover, RP 67580 displayed the profile of a specific antagonist of NK1 receptors: it was not active on NK2 and NK3 receptors as seen in binding assays and in isolated preparations of rabbit pulmonary artery and rat portal vein. In the rat, low intravenous doses of RP 67580 totally inhibited the plasma extravasation induced by SP in the urinary bladder (ED50 = 0.04 mg/kg i.v.) and by antidromic electrical stimulation of the saphenous nerve in the hind paw skin (ED50 = 0.15 mg/kg i.v.). This compound was also active in two classical analgesic tests in mice: phenylbenzoquinone-induced writhing (ED50 = 0.07 mg/kg s.c.) and the formalin test (ED50 = 3.7 mg/kg s.c.). Its potency was of the same order as that of morphine. Thus we conclude that RP 67580, a SP antagonist, belongs to a class of drugs that may be useful in the management of various clinical pathologies where pain and neurogenic inflammation are involved.
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PMID:Pharmacological properties of a potent and selective nonpeptide substance P antagonist. 171 49

The annulus fibrosus of the human intervertebral disc is sparsely innervated, some of the fibers containing substance P. We could demonstrate, by autoradiography, binding sites for substance P localized on the endothelium of small blood vessels in the annulus fibrosus of human intervertebral discs removed during anterior fusion for back pain. In binding inhibition studies, binding of 125I-Bolton Hunter-substance P was inhibited by unlabeled substance P and the related tachykinins neurokinin A and neurokinin B with a rank order of potency substance P > NKA > NKB. Specific binding was reduced > 75 percent by 5'-guanylylimidodiphosphate, indicating G-protein coupling. These features are characteristic of an NK1 receptor through which vascular effects, i.e., vasodilation, plasma extravasation and angiogenesis of substance P, are mediated. The presence of NK1 receptors on blood vessels in the annulus fibrosus may indicate a role for substance P in tissue repair although acute proinflammatory effects may contribute to discogenic pain.
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PMID:Substance P in intervertebral discs. Binding sites on vascular endothelium of the human annulus fibrosus. 753 Aug 90

1. Many studies indicate an involvement of substance P in the transmission of nociceptive stimuli, without, however, presenting any conclusive evidence as to its exact site and mode of action. The present experiments tested the involvement of substance P in the mediation of chemical nociception using the non-peptidic specific tachykinin NK1-receptor antagonist, RP 67580 (2-[1-imino-2-(2-methoxyphenyl-ethyl]-7,7diphenyl-4-perhydroiso indolone (3aR, 7aR)). 2. Mean arterial pressure (MAP) and intragastric pressure (IGP) were measured in anaesthetized rats. The reflex changes of these parameters in response to i.p. or s.c. injections of hydrochloric acid or capsaicin were taken to indicate nociception. 3. Intravenous administration of RP 67580 up to 5 mg kg-1 had little influence on the reflex changes in MAP or IGP in response to hydrochloric acid or capsaicin. In contrast, the sensitization of rats to i.p. capsaicin by preinjection of prostaglandin E2 was significantly reduced by 1 mg kg-1 RP 67580. 4. Intrathecal injection of 5 micrograms RP 67580 inhibited the reflex changes of MAP and IGP in response to i.p. or s.c. capsaicin whereas the inactive enantiomer RP 68651 was ineffective. 5. The results indicate that spinal NK1-receptors are involved in the acute transmission of chemically induced pain, while such receptors in the periphery take part in the sensitization by prostaglandin E2. The rather minor ability of i.v. RP 67580 to inhibit the acute nociceptive reflex is attributed to an insufficient penetration of the blood-brain-barrier.
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PMID:Central versus peripheral site of action of the tachykinin NK1-antagonist RP 67580 in inhibiting chemonociception. 758 61

The tachykinins, substance P, neurokinin A and neurokinin B, are a family of neuropeptides widely distributed in the mammalian central and peripheral nervous system. In the peripheral nervous system, tachykinins released from peripheral endings of sensory nerves are responsible for the neurogenic inflammation phenomenon. In the spinal cord/central nervous system, tachykinins play a role in pain transmission/perception and in some autonomic reflexes and behaviors. Their actions are mediated by three distinct receptors, termed NK1, NK2 and NK3. All tachykinin receptors belong to the superfamily of G protein-coupled receptors, with seven putative transmembrane spanning segments. In the past few years, a number of potent and selective antagonists, of both peptide and nonpeptide nature, has been developed for the NK1, NK2 and NK3 receptors. The contemporary isolation and cloning of the three tachykinin receptors enable now to study the molecular determinants for the interaction of natural tachykinins with their receptors, and the mechanism by which the antagonists interfere in this process. Furthermore, the introduction of tachykinin antagonists has revealed a striking species-related heterogeneity among the tachykinin receptors, and has also suggested a possible intra-species heterogeneity for both NK1 and NK2 receptors. However, molecular biology studies are needed to prove the existence of true tachykinin receptor subtypes.
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PMID:Tachykinin receptors and receptor subtypes. 763 17

This study compared the antinociceptive properties of systemic administration of selective, non-peptidergic antagonists at neurokinin (NK1 and NK2) receptors to those of other classes of antinociceptive agent. (All doses are in mg/kg.) In mice, the NK1 antagonist, CP 99,994, preferentially (inhibitory dose50 (ID50) = 4.4) inhibited the late phase (LP) as compared to the early phase (EP) (16.1) of formalin-induced licking (FIL). A high dose (17.6) elicited ataxia in the rotarod test. Acetic acid-induced writhing was reduced at intermediate doses (10.0) whereas the tail-flick (TF) response to thermal and mechanical stimuli was inhibited only at high doses (22.7 and 17.7, respectively). Modulation of stimulus intensity did not modify the influence of CP 99,994 upon the response to heat. A similar pattern of data was acquired with RP 67,580, although this NK1 antagonist more potently inhibited writhing (2.8). In contrast, RP 68,651, the inactive isomer of RP 67,580, neither reduced the LP of FIL nor modified writhing indicating that these actions of RP 67,580 were stereospecific. Three further NK1 antagonists, SR 140,333, WIN 51,708 and WIN 62,577, likewise inhibited the LP of FIL and failed to modify the TF response at non-ataxic doses. Further, SR 140,333 (0.5) and WIN 51,708 (1.4) were potent ligands in the writhing procedure. The NK2 antagonist, SR 48,966, mimicked NK1 antagonists in preferentially inhibiting the LP (7.7) as compared to the EP (26.9) of FIL. Further, only at doses higher than those evoking ataxia (20.9) did SR 48,968 modify the TF response (36.5 and 32.0 for heat and pressure, respectively). However, it differed to NK1 antagonists in being inactive in the writhing test (> 40.0). In comparison to these NK1 and NK2 antagonists, the mu-opioid agonists (morphine and fentanyl) and kappa-opioid agonists (enadoline and U 69,593) equipotently inhibited all nociceptive responses at doses not provoking ataxia. While the glycine B receptor partial agonist, (+)-HA 966, selectively blocked the LP of FIL and did not evoke ataxia, the NMDA receptor channel blocker, (+)-MK 801, elicited antinociception only at doses close to those provoking ataxia. Finally, the NSAIDs, indomethacin and ibuprofen, the BK2 antagonist, Hoe 140 and the nitric oxide synthase (NOS) inhibitors, L-NAME and 7 nitroindazole, inhibited the LP (but not the EP) of FIL and (except for L-NAME) also reduced writhing: in contrast, they did not evoke ataxia and were inactive in the TF procedures.(ABSTRACT TRUNCATED AT 400 WORDS)
Pain 1995 May
PMID:Antinociceptive profiles of non-peptidergic neurokinin1 and neurokinin2 receptor antagonists: a comparison to other classes of antinociceptive agent. 765 44

Non-peptide ligands for peptide receptors have been discovered in several systems through file screening programs, but the mechanism of action for these candidate drugs is obscure as they do not chemically resemble the native peptides. The compound CP 96345 is a high-affinity, non-peptide antagonist of the substance P (NK1) receptor, which is important in pain perception and neurogenic inflammation. Here we identify epitopes on the NK1 receptor responsible for the specific binding of CP 96345 by systematic exchange of corresponding segments between the NK1 receptor and the homologous NK3 (neurokinin B) receptor, which does not bind the non-peptide ligand. Non-conserved residues, in two epitopes around the top of transmembrane segment V and in one epitope at the top of transmembrane segment VI, are essential for the specific action of CP 96345 on the NK1 receptor, but are surprisingly not important for the binding of the natural peptide ligand, substance P. Susceptibility to the non-peptide antagonists can be conveyed to the previously unresponsive NK3 receptor by mutational transfer of this discontinuous epitope from the NK1 receptor.
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PMID:Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist. 768 Nov 52


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