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)

The spinal cord is one of the sites where non-steroidal anti-inflammatory drugs (NSAIDs) act to produce analgesia and antinociception. Expression of cyclooxygenase(COX)-1 and COX-2 in the spinal cord and primary afferents suggests that NSAIDs act here by inhibiting the synthesis of prostaglandins (PGs). Basal release of PGD(2), PGE(2), PGF(2alpha) and PGI(2) occurs in the spinal cord and dorsal root ganglia. Prostaglandins then bind to G-protein-coupled receptors located in intrinsic spinal neurons (receptor types DP and EP2) and primary afferent neurons (EP1, EP3, EP4 and IP). Acute and chronic peripheral inflammation, interleukins and spinal cord injury increase the expression of COX-2 and release of PGE(2) and PGI(2). By activating the cAMP and protein kinase A pathway, PGs enhance tetrodotoxin-resistant sodium currents, inhibit voltage-dependent potassium currents and increase voltage-dependent calcium inflow in nociceptive afferents. This decreases firing threshold, increases firing rate and induces release of excitatory amino acids, substance P, calcitonin gene-related peptide (CGRP) and nitric oxide. Conversely, glutamate, substance P and CGRP increase PG release. Prostaglandins also facilitate membrane currents and release of substance P and CGRP induced by low pH, bradykinin and capsaicin. All this should enhance elicitation and synaptic transfer of pain signals in the spinal cord. Direct administration of PGs to the spinal cord causes hyperalgesia and allodynia, and some studies have shown an association between induction of COX-2, increased PG release and enhanced nociception. NSAIDs diminish both basal and enhanced PG release in the spinal cord. Correspondingly, spinal application of NSAIDs generally diminishes neuronal and behavioral responses to acute nociceptive stimulation, and always attenuates behavioral responses to persistent nociception. Spinal application of specific COX-2 inhibitors sometimes diminishes behavioral responses to persistent nociception.
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PMID:Prostaglandins and cyclooxygenases [correction of cycloxygenases] in the spinal cord. 1127 57

Prostaglandin E2 (PGE2) is known to be the principal pro-inflammatory prostanoid and play an important role in nociception. To identify PGE receptor (EP) subtypes that mediate pain responses to noxious and innocuous stimuli, we studied them by use of EP1 and EP3 knockout (EP1(-/-) and EP3(-/-)) mice. PGE2 could induce mechanical allodynia in EP1(+/+), EP3(+/+) and EP3(-/-) mice, but not in EP1(-/-) mice. N-methyl-D-aspartate (NMDA), the substrate of nitric oxide (NO) synthase L-arginine, or the NO donor sodium nitroprusside administered intrathecal (i.t.) could induce allodynia in EP3(-/-) and EP1(-/-) mice. Activation of EP1 receptors appears to be upstream, rather than downstream, of NMDA receptor activation and NO production in the PGE2-induced allodynia. Although PGE2 produced thermal hyperalgesia over a wide range of dosages from 50 pg to 0.5 microg kg(-1) in EP3(+/+) mice, it showed a monophasic hyperalgesic action at 5 ng kg(-1) or higher doses in EP3(-/-) mice. The selective EP3 agonist, ONO-AE-248, induced hyperalgesia at 500 pg kg(-1) in EP3(+/+) mice, but not in EP3(-/-) mice. Saline-injected EP1(-/-) mice showed hyperalgesia, which was reversed by i.t. PGE2 in a dose-dependent manner. There was no significant difference in the formalin-induced behaviours between EP1(-/-) or EP3(-/-) mice and the cognate wild-type mice. These results demonstrate that spinal EP1 receptors are involved in the PGE2-induced allodynia and that spinal EP3 receptors are involved in the hyperalgesia induced by low doses of PGE2. However, the formalin-induced pain cannot be ascribed to a single EP receptor subtype EP1 or EP3.
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PMID:Characterization of EP receptor subtypes responsible for prostaglandin E2-induced pain responses by use of EP1 and EP3 receptor knockout mice. 1137 61

The purpose of this study was to investigate the allodynic effect of bicuculline (BIC) given topically to the dorsal surface of the rat spinal cord, and to determine if spinal prostaglandins (PGs) mediate the allodynic state arising from spinal GABA(A)-receptor blockade. Male Sprague-Dawley rats (325-400 g) were anaesthetized with halothane and maintained with urethane for the continuous monitoring of blood pressure (MAP), heart rate (HR) and cortical electroencephalogram (EEG). A laminectomy was performed to expose the dorsal surface of the spinal cord. Unilateral application of BIC (0.1 microg in 0.1 microl) to the L5 or L6 spinal segment induced a highly localized allodynia (e.g. one or two digits) on the ipsilateral hind paw. Thus, hair deflection (brushing the hair with a cotton-tipped applicator) in the presence, but not absence of BIC, evoked an increase in MAP and HR, abrupt motor responses (MR; e.g. withdrawal of the hind leg, kicking, and/or scratching) on the affected side, and desynchrony of the EEG. BIC-allodynia was dose-dependent, yielding ED(50)'s (95% CI's) of 45 ng (31-65) for MAP; 68 ng (46-101) for HR and 76 ng (60-97) for MR. Allodynia was sustained for up to 2 h with repeated BIC application without any detectable change in the location or area of peripheral sensitization. Pretreatment with either the EP(1)- receptor antagonist, SC-51322, the cyclooxygenase (COX)-2 selective inhibitor, NS-398, or the NMDA-receptor antagonist, AP-7, inhibited BIC-allodynia in a dose-dependent manner. The results demonstrate: (a) BIC, applied to the dorsal surface of the spinal cord, induces highly localized allodynia; (b) this effect can be sustained with repeated BIC application; (c) it is evoked by NMDA-dependent afferent input; (d) spinal PGs are synthesized by constitutive COX-2 during BIC-allodynia; and (e) spinal PGs contribute to the abnormal processing of tactile input via spinal EP1-receptors.
Pain 2001 Jun
PMID:Topical bicuculline to the rat spinal cord induces highly localized allodynia that is mediated by spinal prostaglandins. 1137 8

We previously reported that cyclooxygenase 2 (COX2) is up-regulated in macrophages in injured nerve of rats with partial sciatic nerve ligation (PSNL) and that local injection of the COX inhibitor ketorolac reversed tactile allodynia (Eur. J. Neurosci. 15: 1037-1047, 2002). These findings suggest that prostaglandins (PGs) are overproduced in injured nerve and are involved in the pathogenesis of neuropathic pain. In this study, we examined whether overproduced PGs alter the expression of PGE2 receptors, EP1-EP4, in injured nerve of PSNL rats. We found that cell profiles immunoreactive (IR) for four EP receptors, EP1, EP2, EP3, and EP4, are dramatically increased in injured nerve 2 and 4 weeks after PSNL. EP4-IR cells were the most abundant among these receptor-expressing cells. Immunoreactivities of all four EP receptors were localized to the cell nucleus. These EP-IR cells were never found in uninjured nerve. More than 80% EP1- and about 30% EP4-IR cells were identified as infiltrating macrophages since they coexpressed ED1. Only 3% EP2- and 6% EP3-IR cells coexpressed ED1. These findings suggest that majority of EP2-, EP3-, and EP4-IR cells are other types of inflammatory cells than macrophages. About 48% of macrophages expressed EP1 and 45% expressed EP4. Only 3 and 6% of macrophages, respectively, expressed EP2 and EP3. Perineural injection of ketorolac reversed tactile allodynia and suppressed the up-regulation of EP1 and EP4, but not the recruitment of ED1-IR marcrophages, in injured nerve. Our data suggest that following PSNL, PGE2 is one of the possible PGs overproduced in injured nerve and PG overproduction is involved in the up-regulation of EP receptors in injured nerve.
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PMID:Four PGE2 EP receptors are up-regulated in injured nerve following partial sciatic nerve ligation. 1455 99

Inflammatory pain is caused by sensitization of peripheral and central nociceptive neurons. Prostaglandins substantially contribute to neuronal sensitization at both sites. Prostaglandin E2 (PGE2) applied to the spinal cord causes neuronal hyperexcitability similar to peripheral inflammation. Because PGE2 can act through EP1-EP4 receptors, we addressed the role of these receptors in the spinal cord on the development of spinal hyperexcitability. Recordings were made from nociceptive dorsal horn neurons with main input from the knee joint, and responses of the neurons to noxious and innocuous stimulation of the knee, ankle, and paw were studied after spinal application of recently developed specific EP1-EP4 receptor agonists. Under normal conditions, spinal application of agonists at EP1, EP2, and EP4 receptors induced spinal hyperexcitability similar to PGE2. Interestingly, the effect of spinal EP receptor activation changed during joint inflammation. When the knee joint had been inflamed 7-11 hr before the recordings, only activation of the EP1 receptor caused additional facilitation, whereas spinal application of EP2 and EP4 receptor agonists had no effect. Additionally, an EP3alpha receptor agonist reduced responses to mechanical stimulation. The latter also attenuated spinal hyperexcitability induced by spinal PGE2. In isolated DRG neurons, the EP3alpha agonist reduced the facilitatory effect of PGE2 on TTX-resistant sodium currents. Thus pronociceptive effects of spinal PGE2 can be limited, particularly under inflammatory conditions, through activation of an inhibitory splice variant of the EP3 receptor. The latter might be an interesting target for controlling spinal hyperexcitability in inflammatory pain states.
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PMID:Changes in the effect of spinal prostaglandin E2 during inflammation: prostaglandin E (EP1-EP4) receptors in spinal nociceptive processing of input from the normal or inflamed knee joint. 1473 50

Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPV1 is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPV1 has been reported to be critical for inflammatory pain mediated through PKA- and PKC-dependent pathways. PGE2 or PGI2increased or sensitized TRPV1 responses through EP1 or IP receptors, respectively predominantly in a PKC-dependent manner in both HEK293 cells expressing TRPV1 and mouse DRG neurons. In the presence of PGE2 or PGI2, the temperature threshold for TRPV1 activation was reduced below 35 degrees C, so that temperatures near body temperature are sufficient to activate TRPV1. A PKA-dependent pathway was also involved in the potentiation of TRPV1 through EP4 and IP receptors upon exposure to PGE2 and PGI2, respectively. Both PGE2-induced thermal hyperalgesia and inflammatory nociceptive responses were diminished in TRPV1-deficient mice and EP1-deficient mice. IP receptor involvement was also demonstrated using TRPV1-deficient mice and IP-deficient mice. Thus, the potentiation or sensitization of TRPV1 activity through EP1 or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE2 or PGI2.
Mol Pain 2005 Jan 17
PMID:Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. 1581 89

The mechanisms underlying neuropathic pain caused by nerve injury are not well understood. Inflammatory responses in injured nerves are likely to be key contributing factors in the generation and maintenance of neuropathic pain. The pro-inflammatory cytokine interleukin-6 (IL-6) is up-regulated in invading macrophages and has been implicated in the development of neuropathic pain. We previously demonstrated that invading macrophages up-regulate cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) receptors EP1 and EP4, suggesting that PGE2 may affect macrophage function via autocrine or paracrine mechanisms. This study was undertaken to determine whether PGE2 is involved in the up-regulation of IL-6 in invading macrophages. Two weeks following partial sciatic nerve ligation, numerous IL-6 immunoreactive (IR) cell profiles were present in injured nerves. Colocalization of IL-6 with the invading macrophage marker ED1 or with COX2 was frequently observed. IL-6-IR, COX2-IR and ED1-IR cells were present only in cultures derived from injured nerve segments. PGE2 and IL-6 release from cultured cells derived from injured nerves was increased significantly compared with uninjured nerves. Non-selective and selective COX2 inhibitors suppressed PGE2 and IL-6 release. Treatment with PGE2 further enhanced IL-6 release in a concentration- and time-dependent manner. A selective EP4 receptor antagonist L-161982 was able to suppress IL-6 release, whereas an EP1 receptor antagonist, SC19220, was ineffective. Moreover, a protein kinase C inhibitor, calphostin C, dramatically suppressed IL-6 release, whereas a protein kinase A inhibitor H-89 and a Ca2+ chelator EGTA failed. Taken together, our data suggest that PGE2 is involved in mediating the up-regulation of IL-6 occurring in invading macrophages. This action is mediated through an EP4 receptor and the protein kinase C signaling pathway.
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PMID:Up-regulation of interleukin-6 induced by prostaglandin E from invading macrophages following nerve injury: an in vivo and in vitro study. 1583 25

The precise mechanisms of zoster-associated pain and postherpetic neuralgia remain unknown. Inoculation of mice with herpes simplex virus type-1 elicits acute herpetic pain- and delayed postherpetic pain-related responses. We investigated the role of prostaglandins (PGs) and their synthases in both types of pain. Deficiency in EP3 but not EP1, IP or TP prostanoid receptor markedly diminished the acute herpetic pain and resulted in the decrease of the incidence of the delayed postherpetic pain. Preventive but not therapeutic administration of the EP3 antagonist ONO-AE3-240 inhibited the acute herpetic pain. The non-selective cyclooxygenase (COX) inhibitor diclofenac and the selective COX-2 inhibitors NS-398 and JTE-522 dose dependently reduced the acute herpetic pain, and NS-398 was without effect on delayed postherpetic pain. COX-2 was induced and PGE2 content was increased in the affected dorsal root ganglia at the stage of acute herpetic pain. COX-2-like immunoreactivities were found around the nuclear membrane of many dorsal root ganglion neurons that were negative for herpesvirus antigen. COX-2 mRNA expression and PGE2 content in the affected dorsal root ganglia at the stage of delayed postherpetic pain were similar to those of naive mice. The propagation of herpes virus in dorsal root ganglion may induce COX-2 and produce PGE2 in uninfected neurons. The results suggest the important roles of COX-2 induction and the PGE2-EP3 receptor system in the dorsal root ganglia in the development but not maintenance of acute herpetic pain. It was further confirmed that the PG systems do not play a key role in delayed postherpetic pain.
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PMID:Involvement of cyclooxygenase-2 and EP3 prostaglandin receptor in acute herpetic but not postherpetic pain in mice. 1592 91

Prostaglandin E2 (PGE2), the principal pro-inflammatory prostanoid, is known to play versatile roles in pain transmission via four PGE receptor subtypes, EP1-EP4. We recently demonstrated that continuous production of nitric oxide (NO) by neuronal NO synthase (nNOS) following phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) and NMDA receptor NR2B subunits is essential for neuropathic pain. These phosphorylation and nNOS activity visualized by NADPH-diaphorase histochemistry were blocked by indomethacin, a PG synthesis inhibitor. To clarify the interaction between cyclooxygenase and nNOS pathways in the spinal cord, we examined the effect of EP subtype-selective agonists on NO production. NO formation was stimulated in the spinal superficial layer by EP1, EP3, and EP4 agonists. While the EP1- and the EP4-stimulated NO formation was markedly blocked by MK-801, an NMDA receptor antagonist, the EP3-stimulated one was completely inhibited by H-1152, a Rho-kinase inhibitor. Phosphorylation of MARCKS and NADPH-diaphorase activity stimulated by the EP3 agonist were also blocked by H-1152. These results suggest that PGE2 stimulates NO formation by Rho-kinase via EP3, a mechanism(s) different from EP1 and EP4.
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PMID:Rho-kinase mediates spinal nitric oxide formation by prostaglandin E2 via EP3 subtype. 1618 27

Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.
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PMID:Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain. 1619 Aug 98


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