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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotoxins affecting neuroexocytosis can represent an innovative pharmacological approach to the investigation of neural mechanisms of pain. Our interest has been focused on the use of botulinum neurotoxins (BoNTs), whose peripheral effects are extensively documented, while the effects on the central nervous system are much less clear. We have investigated both peripheral (sc into the hindpaw) and central (icv) effects of two BoNTs isoforms, BoNT/A and BoNT/B, on inflammatory pain. BoNT/A (sc: 0.937-15; icv: 0.937-3.75 pgtox/mouse) and BoNT/B (sc: 3.75, 7.5; icv: 1.875, 3.75 pgtox/mouse) were injected in CD1 mice and tested in the formalin test 3 days later. Licking response, as index of pain, and behavioral parameters, such as general activity and grooming, were recorded for 40 min during the test. BoNT/A partially affects the licking response in the second phase of formalin test in a similar magnitude of attenuation whether peripherally or centrally administered. BoNT/A does not significantly affect licking behavior during the first phase of the test. Peripheral administration of BoNT/B attenuates the licking response during the first phase not modifying the second phase, while the icv administration has hyperalgesic effect on the interphase of the formalin test. General activity and grooming behavior are not affected either by peripheral or by central administration of BoNTs. Our results show for the first time a central effect of BoNTs that differently modulate inflammatory pain depending both on serotype and on route of administration. Such data suggest BoNTs as a useful tool in the studies aimed at the comprehension of the mechanisms of inflammatory pain.
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PMID:Botulinum neurotoxins and formalin-induced pain: central vs. peripheral effects in mice. 1652 62

The pain modulatory properties of melatonin (MT) are generally recognized but the detail of the interaction between melatonin and opioid system in pain regulation is not fully understood. The present study was undertaken to investigate the modulatory effect of melatonin (MT) on the hyperalgesic effect of Orphanin FQ/Nociceptin (OFQ/NC, NC), a member of opioid peptide family. Intracerebroventricular (i.c.v.) administration of NC (10 microg/mouse) induced significant hyperalgesic effect in tail-flick test in mice; i.c.v. (5, 10, 50 microg/mouse) or intraperitoneal (i.p.) (5, 10, 50 mg/kg) co-injection of melatonin dose-dependently reversed NC-induced hyperalgesia and showed a profound analgesic effect. The antihyperalgesia effect of MT could be significantly antagonized by i.c.v. co-injection of luzindole (10 microg/mouse) (an antagonist of MT receptor) or naloxone (10 microg/mouse) (antagonist of traditional opioid receptor). Taken together, all the results suggested that MT could produce a luzindole and naloxone sensitive reversing effect on NC-induced hyperalgesia at supraspinal and peripheral level in mice. The augmentation effect of MT on the traditional opioid system may be one of the mechanisms of this antihyperalgesia action induced by MT. The present work will help to elucidate the mechanism of the pain modulation effect of MT, and also will help to represent new interesting modulating therapeutic targets for the relief of pain.
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PMID:Effects of melatonin on orphanin FQ/nociceptin-induced hyperalgesia in mice. 1656 6

Nociceptin/orphanin FQ (N/OFQ) has been demonstrated to modulate nociceptive transmission via selective activation of N/OFQ peptide (NOP) receptors. Despite huge research efforts, the role(s) of the endogenous N/OFQ-NOP receptor system in pain processing remains incompletely understood. In the present study, we investigated the role of endogenous N/OFQ in the processing of tonic nociceptive input. To address this issue the effects of NOP-selective antagonists [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) and J-113397 on nociceptive behaviour, and the nociceptive phenotype of NOP receptor-deficient mice were tested in the mouse formalin test. Twenty microliters of 1.5% formalin solution was injected subcutaneously into the right hind paw causing a characteristic pattern of nociceptive behaviours (licking, biting and lifting of the injected paw). In control mice, the injection of formalin resulted in a classical biphasic nociceptive response with the first phase lasting from 0 to 10 min and the second phase from 15 to 45 min. UFP-101 at 10 nmol/mouse (but not at 1 nmol/mouse) produced antinociceptive action when injected intracerebroventricularly and a pronociceptive action when given intrathecally. Systemic administration of J-113397 (10 mg/kg, intravenously) and the genetic ablation of the NOP receptor gene both produced a significant increase of mouse nociceptive behaviour. Collectively, these results demonstrate that endogenous N/OFQ-NOP receptor signalling is activated during the mouse formalin test producing spinal antinociceptive and supraspinal pronociceptive effects. The overall effect of blocking NOP receptor signalling, by either systemic pharmacological antagonism or genetic ablation, indicates that the spinal antinociceptive action prevails over supraspinal pronociceptive effects.
Pain 2006 Sep
PMID:Endogenous nociceptin/orphanin FQ signalling produces opposite spinal antinociceptive and supraspinal pronociceptive effects in the mouse formalin test: pharmacological and genetic evidences. 1669 9

CART peptides are found in brain and spinal cord areas involved in pain transmission. In the present study, we investigated the role of rat CART (55-102) in the modulation of chronic pain using models of chronic neuropathic (nerve injury model) and inflammatory (carrageenan test) pain models in the mouse after intrathecal administration. The results show that CART (55-102) was highly effective in reversing the hyperalgesia and allodynia signs of chronic neuropathic pain in a dose-related manner at doses (0.05-2 microg/mouse) that did not affect motor coordination of the animals. These effects lasted for at least 3 h after injection and were not blocked by naloxone, an opiate antagonist. Although CART (55-102) attenuated carrageenan-induced hyperalgesia, it failed to reduce the inflammation associated with this model. These results suggest the involvement of the CART peptides in the development of hyperalgesia and allodynia associated with neuropathic pain.
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PMID:Intrathecal CART (55-102) attenuates hyperlagesia and allodynia in a mouse model of neuropathic but not inflammatory pain. 1681 1

In spite of prominent progress in basic pain research, neuropathic pain remains a significant medical problem, because it is often poorly relieved by conventional analgesics. Thus this situation encourages us to make more sophisticated efforts toward the discovery of new analgesics. We previously showed that i.t. administration of acromelic acid-A (ACRO-A), a Japanese mushroom poison, provoked prominent tactile pain (allodynia) at an extremely low dose of 1 fg/mouse. In the present study we synthesized ACRO-A analogues (2S,3R,4R)-3-carboxymethyl-4-phenoxypyrrolidine-2-carboxylic acid (POPA-2) and (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1) chemically and examined their ability to induce allodynia in conscious mice. Whereas POPA-2 induced allodynia at extremely low doses from 1 to 100 fg/mouse, similar to ACRO-A, PSPA-1 did not induce allodynia; rather, it inhibited the ACRO-A-induced allodynia with an ID(50) value (95% confidence limits) of 2.19 fg/mouse (0.04-31.8 fg/mouse). Furthermore, PSPA-1 relieved neuropathic pain produced by L5 spinal nerve transection on day 7 after the operation in a dose-dependent manner from 1 to 100 pg/mouse. In contrast, it did not affect thermal or mechanical nociception or inflammatory pain. PSPA-1 reduced the increase in neuronal nitric oxide synthase activity in the spinal cord of neuropathic pain mice assessed by NADPH-diaphorase histochemistry and blocked the allodynia induced by N-methyl-d-aspartate. These results demonstrate that PSPA-1 may represent a novel class of anti-allodynic agents for neuropathic pain acting by blocking the glutamate-nitric oxide pathway.
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PMID:A synthetic kainoid, (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1) serves as a novel anti-allodynic agent for neuropathic pain. 1782 64

Human hemokinin-1 (h HK-1) and its truncated form h HK-1(4-11) are mammalian tachykinin peptides encoded by the recently identified TAC4 gene in human, and the biological functions of these peptides have not been well investigated. In the present study, an attempt has been made to investigate the effects and mechanisms of action of h HK-1 and h HK-1(4-11) in pain modulation at the supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of h HK-1 (0.3, 1, 3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the NK(1) receptor antagonist SR140333, but not by the NK(2) receptor antagonist SR48968, indicating that the analgesic effect induced by i.c.v. h HK-1 is mediated through the activation of NK(1) receptors. Interestingly, naloxone, beta-funaltrexamine and naloxonazine, but not naltrindole and nor-binaltorphimine, could also block the analgesic effect markedly, suggesting that this effect is related to descending mu opioidergic neurons (primary mu(1) subtype). Human HK-1(4-11) could also induce a dose- and time-dependent analgesic effect after i.c.v. administration, however, the potency of analgesia was less than h HK-1. Surprisingly, SR140333 could not modify this analgesic effect, suggesting that this effect is not mediated through the NK(1) receptors like h HK-1. SR48968 could modestly enhance the analgesic effect induced by h HK-1(4-11), indicating that a small amount of h HK-1(4-11) may bind to NK(2) receptors. Furthermore, none of the opioid receptor (OR) antagonists could markedly block the analgesia of h HK-1(4-11), suggesting that the analgesic effect is not mediated through the descending opioidergic neurons. Blocking of delta ORs significantly enhanced the analgesia, indicating that delta OR is a negatively modulatory factor in the analgesic effect of h HK-1(4-11). It is striking that bicuculline (a competitive antagonist at GABA(A) receptors) effectively blocked the analgesia induced by h HK-1(4-11), suggesting that this analgesic effect is mediated through the descending inhibitory GABAergic neurons. The novel mechanism involved in the analgesic effect of h HK-1(4-11), which is different from that of h HK-1, may pave the way for a new strategy for the investigation and control of pain.
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PMID:In vivo characterization of the effects of human hemokinin-1 and human hemokinin-1(4-11), mammalian tachykinin peptides, on the modulation of pain in mice. 1826 87

We have previously reported that serotonin concentration was reduced in the brain of mice with neuropathic pain and that it may be related to reduction of morphine analgesic effects. To further prove this pharmacological action, we applied fluoxetine, a selective serotonin reuptake inhibitor, to determine whether it suppressed neuropathic pain and examined how its different administration routes would affect antinociceptive and antiallodynic effects of morphine in diabetic (DM) and sciatic nerve ligation (SL) mice, as models of neuropathic pain. Antiallodynia and antinociceptive effect of drugs were measured by using von Frey filament and tail pinch tests, respectively. Fluoxetine given alone, intracerebroventicularly (i.c.v., 15 microg/mouse) or intraperitoneally (i.p., 5 and 10 mg/kg) did not produce any effect in either model. However, fluoxetine given i.p. enhanced both antiallodynic and antinociceptive effects of morphine. Administration of fluoxetine i.c.v., slightly enhanced only the antiallodynic effect of morphine in SL mice. Ketanserine, a serotonin 2A receptor antagonist (i.p., 1 mg/kg) and naloxone, an opioid receptor antagonist (i.p., 3 mg/kg), blocked the combined antinociceptive effect of fluoxetine and morphine. Our data show that fluoxetine itself lacks antinociceptive properties in the two neuropathy models, but it enhances the analgesic effect of morphine in the periphery and suggests that co-administration of morphine with fluoxetine may have therapeutic potential in treatment of neuropathic pain.
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PMID:Modification of antiallodynic and antinociceptive effects of morphine by peripheral and central action of fluoxetine in a neuropathic mice model. 1827 63

We sought to examine the involvement of central cannabinoid CB2 receptor activation in modulating mechanical allodynia in a mouse model of neuropathic pain. JWH133 was demonstrated to be a selective cannabinoid CB2 receptor agonist in mice, reducing forskolin-stimulated cAMP production in CHO cells expressing mouse cannabinoid CB2 and cannabinoid CB1 receptors with EC50 values of 63 nM and 2500 nM, respectively. Intrathecal administration of JWH133 (50 and 100 nmol/mouse) significantly reversed partial sciatic nerve ligation-induced mechanical allodynia in mice at 0.5 h after administration. In contrast, systemic (intraperitoneal) or local (injected to the dorsal surface of the hindpaw) administration of JWH133 (100 nmol/mouse) was ineffective. Furthermore, the analgesic effects of intrathecal JWH133 (100 nmol/mouse) were absent in cannabinoid CB2 receptor knockout mice. These results suggest that the activation of central, but not peripheral, cannabinoid CB2 receptors play an important role in reducing mechanical allodynia in a mouse model of neuropathic pain.
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PMID:Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain. 1827 50

A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).
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PMID:Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models. 1881 67

The effect of apelin-13 on pain modulation at the supraspinal level was investigated in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of apelin-13 (0.3, 0.5, 0.8 and 3 microg/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the APJ receptor antagonist apelin-13(F13A), indicating an APJ receptor-mediated mechanism. Furthermore, naloxone, beta-funaltrexamine and naloxonazine, could reverse the analgesic effect. However, naltrindole or nor-binaltorphimine could not reverse the effect, suggesting that mu opioid receptor (primarily mu(1) opioid receptor subtype) is involved in the analgesic response evoked by apelin-13. Moreover, i.c.v. administration of apelin-13 potentiated the analgesic effect induced by morphine (i.c.v., 5 microg/kg) and this potentiated effect can be also reversed by naloxone.
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PMID:Supraspinal administration of apelin-13 induces antinociception via the opioid receptor in mice. 1946 49


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