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)

Activation of P2X(3) and P2X(2/3) receptors (P2X(3)R/P2X(2/3)R), ionotropic ATP receptor subtypes, in primary sensory neurons is involved in neuropathic pain, a debilitating chronic pain that occurs after peripheral nerve injury. However, the underlying mechanisms remain unknown. We investigated the role of cytosolic phospholipase A(2) (cPLA(2)) as a downstream molecule that mediates the P2X(3)R/P2X(2/3)R-dependent neuropathic pain. We found that applying ATP to cultured dorsal root ganglion (DRG) neurons increased the level of Ser505-phosphorylated cPLA(2) and caused translocation of Ser505-phosphorylated cPLA(2) to the plasma membrane. The ATP-induced cPLA(2) activation was inhibited by a selective antagonist of P2X(3)R/P2X(2/3)R and by a selective inhibitor of cPLA(2). In the DRG in vivo, the number of cPLA(2)-activated neurons was strikingly increased after peripheral nerve injury but not after peripheral inflammation produced by complete Freund's adjuvant. Pharmacological blockade of P2X(3)R/P2X(2/3)R reversed the nerve injury-induced cPLA(2) activation in DRG neurons. Moreover, administering the cPLA(2) inhibitor near the DRG suppressed nerve injury-induced tactile allodynia, a hallmark of neuropathic pain. Our results suggest that P2X(3)R/P2X(2/3)R-dependent cPLA(2) activity in primary sensory neurons is a key event in neuropathic pain and that cPLA(2) might be a potential target for treating neuropathic pain.
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PMID:P2X receptors-mediated cytosolic phospholipase A2 activation in primary afferent sensory neurons contributes to neuropathic pain. 1772 79

The cytolytic ionotropic ATP receptor P2X7 has several important roles in immune cell regulation, such as cytokine release, apoptosis, and microbial killing. Although P2X7 receptors are frequently coexpressed with another subtype of P2X receptor, P2X4, they are believed not to form heteromeric assemblies but to function only as homomers. Both receptors play a role in neuropathic pain; therefore, understanding how they coordinate the cellular response to ATP is important for the development of effective pain therapies. Here, we provide biochemical and electrophysiological evidence for an association between P2X4 and P2X7 that increases the diversity of receptor currents mediated via these two subtypes. The heterologously expressed receptors were coimmunoprecipitated from human embryonic kidney (HEK) 293 cells, and the endogenous P2X4 and P2X7 receptors were similarly coimmunoprecipitated from bone marrow-derived macrophages. In HEK293 cells, the fraction of P2X4 receptors biotinylated at the plasma membrane increased 2-fold in the presence of P2X7 although there was no change in overall expression. Coexpression of a dominant-negative P2X4 mutant (C353W) with P2X7, inhibited P2X7 receptor mediated currents by greater than 2-fold, whereas a nonfunctional but non-dominant-negative mutant (S341W) did not. Coexpression of P2X4S341W with P2X7 produced a current that was potentiated by ivermectin and inhibited by 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate (TNP-ATP), whereas expression of P2X7 alone produced a current that was insensitive to both of these compounds at the concentrations used. These results demonstrate a structural and functional interaction between P2X4 and P2X7, which suggests that they associate to form heteromeric receptors.
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PMID:Evidence for functional P2X4/P2X7 heteromeric receptors. 1789 6

Recent advances have shed insight on the pathophysiologic mechanisms of fibromyalgia and migraine, especially in the chronic form. A growing body of evidence supports the involvement of peripheral and central sensitization disturbances of pain-related processes underlying both disorders. They involve increased glutamate transmission through interaction with its ionotropic and metabotropic receptors. Few studies supporting the implication of this excitatory amino acid in chronic migraine and primary fibromyalgia demonstrated increased levels of glutamate in the cerebrospinal fluid of affected patients. These findings have implications for future therapies directed against glutamate receptors (in particular, N-methyl-D-aspartate receptors). Limited clinical experience in this regard, although promising, does not exclude additional mechanisms contributing to the maintenance of pain, which can be the target of therapeutic approaches in both disorders.
Curr Pain Headache Rep 2007 Oct
PMID:Sensitization, glutamate, and the link between migraine and fibromyalgia. 1789 24

Glutamate plays a key role in modulation of nociceptive processing. This excitatory amino acid exerts its action through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluRs). Eight mGluRs have been identified and divided in three groups based on their sequence similarity, pharmacology and G-protein coupling. While the role of group I and II mGluRs is now well established, little is known about the part played by group III mGluRs in pain. In this work, we studied comparatively the involvement of spinal group III mGluR in modulation of acute, inflammatory and neuropathic pain. While intrathecal injection of ACPT-I, a selective group III mGluR agonist, failed to induce any change in vocalization thresholds of healthy animals submitted to mechanical or thermal stimuli, it dose-dependently inhibited the nociceptive behavior of rats submitted to the formalin test and the mechanical hyperalgesia associated with different animal models of inflammatory (carrageenan-treated and monoarthritic rats) or neuropathic pain (mononeuropathic and vincristine-treated rats). Similar effects were also observed following intrathecal injection of PHCCC, a positive allosteric modulator of mGlu4. Antihyperalgesia induced by ACPT-I was blocked either by LY341495, a nonselective antagonist of mGluR, by MAP4, a selective group III antagonist. This study provide new evidences supporting the role of spinal group III mGluRs in the modulation of pain perception in different pathological pain states of various etiologies but not in normal conditions. It more particularly highlights the specific involvement of mGlu4 in this process and may be a useful therapeutic approach to chronic pain treatment.
Pain 2008 Jul
PMID:Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain. 1790 Aug 8

Neuropathic pain, a debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. One hallmark is abnormal pain hypersensitivity to innocuous stimuli (tactile allodynia), for which effective therapy is lacking, and the underlying mechanisms of which remain to be determined. Here we show that Lyn, a member of the Src family kinases (SFKs), plays an important role in the pathogenesis of neuropathic pain. Nerve injury, but not peripheral inflammation, increased immunoreactivity for active SFKs that were autophosphorylated in the kinase domain (phospho-SFK-IR) in spinal microglia. In spinally derived microglial cells, we identified Lyn as the predominant SFK among the five members (Src, Fyn, Yes, Lck, and Lyn) known to be expressed in the CNS. Lyn expression in the spinal cord was highly restricted to microglia, and its level was increased after nerve injury. We found that mice lacking lyn (lyn(-/-)) exhibit a striking reduction in the levels of phospho-SFK-IR and tactile allodynia after nerve injury, without any change in basal mechanical sensitivity or inflammatory pain. Importantly, lyn(-/-) mice displayed impaired upregulation of the ionotropic ATP receptor subtype P2X(4) receptors (P2X(4)R) in the spinal cord after nerve injury, which is crucial for tactile allodynia. Microglial cells from lyn(-/-) mice showed a deficit in their ability to increase P2X(4)R expression in response to fibronectin, a factor implicated as a microglial P2X(4)R upregulator in allodynia. Together, our findings suggest that Lyn may be a critical kinase mediating nerve injury-induced P2X(4)R upregulation and neuropathic pain.
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PMID:Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury. 1791 63

Glutamate is a major excitatory neurotransmitter in central nervous system (CNS) acting through ionotropic and G-protein coupled metabotropic glutamate receptors. Metabotropic glutamate receptor 5 (mGluR5), a subtype in the group I mGluRs, presents in high density in many brain regions (hippocampus, cortex and olfactory system). Stimulation of mGluR5 leads to the release of calcium from intracellular supplies and protein kinase C activation. Excessive activation of mGluR5 has been associated with psychiatric, neurological and neurodegenerative diseases, including Parkinson's disease, anxiety, depression, schizophrenia, pain, epilepsy, focal and global ischemia diseases. 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 2-methyl-4-(pyridin-3-ylethynyl)thiazole (MTEP) are the first generation of non-competitive mGluR5 antagonists with potent, selective and systemically active properties. They have therapeutic functions in varied diseases. Investigation of mGluR5 physiological functions under pathologic conditions in patients will be critically important in mGluR5 antagonist's therapy using noninvasive positron emission tomography (PET) imaging technique. There are eleven mGluR5 imaging PET tracers have been tested in animal studies. This article highlights efforts on the design and development of novel PET tracers for mGluR5 in vivo imaging.
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PMID:Recent developments of the PET imaging agents for metabotropic glutamate receptor subtype 5. 1797 88

Glutamate spillover regulates GABAergic synaptic transmission at several CNS synapses via presynaptic ionotropic and metabotropic glutamate receptors (mGluRs). We have previously demonstrated that activation of group I-III mGluRs inhibits GABAergic transmission in the midbrain periaqueductal gray (PAG), a region involved in organizing behavioral responses to threat, stress, and pain. Here, we examined the role of glutamate spillover in the modulation of GABAergic transmission in the PAG. Using whole-cell recordings from rat PAG slices, we found that evoked IPSCs were reduced by the nonspecific glutamate transport blockers DL-threo-beta-benzyloxyaspartic acid (TBOA) and L-trans-pyrrolidine-2,4-dicarboxylic acid, but not by the glial GLT1-specific blocker dihydrokainate. In contrast, TBOA had no effect on evoked IPSCs when glutamate uptake into the postsynaptic neuron was selectively impaired. TBOA increased the paired-pulse ratio of evoked IPSCs and reduced the rate but not the amplitude of spontaneous miniature IPSCs. The effect of TBOA on evoked IPSCs was abolished by the broad-spectrum mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (100 microM), reduced by the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and mimicked by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the effects of both TBOA and DHPG were reduced by the cannabinoid CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251). Finally, although MPEP and AM251 had no effect on single evoked IPSCs, they increased evoked IPSCs during repetitive stimulation. These results indicate that neuronal glutamate transporters limit mGluR5 activation and endocannabinoid signaling, but may be overwhelmed during conditions of elevated glutamate release. Thus, neuronal glutamate transporters play a key role in regulating endocannabinoid-mediated cross talk between glutamatergic and GABAergic synapses within the PAG.
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PMID:Glutamate spillover modulates GABAergic synaptic transmission in the rat midbrain periaqueductal grey via metabotropic glutamate receptors and endocannabinoid signaling. 1821 89

The effect of the non-selective, 1-aminoindan-1,5-dicarboxylic acid (AIDA), and selective (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone (JNJ16259685), metabotropic glutamate subtype 1 (mGlu1) receptor antagonists, on rat sciatic nerve chronic constrictive injury (CCI)-induced hyperalgesia, allodynia, spinal dorsal horn apoptosis, and gliosis was examined at 3 and 7 days post-injury. RT-PCR analysis showed increased expression of bax, apoptotic protease-activating factor-1 (apaf-1), nestin, GFAP, and caspase-7 mRNA in the dorsal horn spinal cord by 3 days post-CCI. At 7 days post-CCI, only over-expression of bcl-2, nestin and GFAP mRNA was observed. Administration of AIDA reduced thermal hyperalgesia and mechanical allodynia at 3 and 7 days post-CCI; administration of JNJ16259685 reduced thermal hyperalgesia at 3 and 7 days post-CCI, but not mechanical allodynia. AIDA decreased the mRNA levels of bax, apaf-1, GFAP and caspase-7 genes. JNJ16259685 increased the mRNA levels of bcl-2 and GFAP gene, and decreased APAF-1 and caspases-7 genes. Inhibiting mGlu1 receptors also reduced TUNEL-positive profiles and immunohistochemical reactivity for caspase-7. We report here that despite inhibiting CCI-induced over-expression of pro-apoptotic genes in the spinal cord dorsal horn, the selective mGlu1 receptor antagonist JNJ16259685 exerted only a slight and transient allodynic effect. Moreover, JNJ16259685, but not the non-selective AIDA, increased astrogliosis which may account for its decreased analgesic efficacy. This study provides evidence that the contemporary and partial blockade of group I and likely ionotropic glutamate receptors may be a more suitable therapy than selective blockade of mGlu1 subtype receptors condition to decrease neuropathic pain symptoms.
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PMID:Involvement of subtype 1 metabotropic glutamate receptors in apoptosis and caspase-7 over-expression in spinal cord of neuropathic rats. 1832 79

Good evidence exists to suggest that individuals on opioid maintenance for the treatment of addiction (i.e. methadone) are less tolerant of experimental pain than are matched controls or ex-opioid addicts, a phenomenon theorized to reflect opioid-induced hyperalgesia (OIH). Agonist activity at the excitatory ionotropic N-methyl-D-aspartate (NMDA) receptor on dorsal horn neurons has been implicated in the development of both OIH and its putative expression at the clinical level-opioid tolerance. The aim of this study was to evaluate the potential utility of the NMDA-receptor antagonist, dextromethorphan (DEX), to reverse or treat OIH in methadone-maintenance (MM) patients. Utilizing a clinical trial design and double-blind conditions, changes in pain threshold and tolerance [cold pressor (CP) and electrical stimulation (ES)] following a 5-week trial of DEX (titrated to 480 mg/day) in comparison with placebo was evaluated in a well-characterized sample of MM patients. The sample (n = 40) was 53% male and ethnically diverse (53% Latino, 28% African American, 10% White, 9% other), with a mean age of 48.0 years (SD = 6.97). Based on t-test analyses, no difference was found between groups on CP pain threshold, CP pain tolerance, ES pain threshold or ES pain tolerance, both pre- and postmedication. Notably, DEX-related changes significantly differed by gender, with women tending to show diminished tolerance for pain with DEX therapy. These results support that chronic high-dose NMDA antagonism does not improve tolerance for pain in MM patients, although a gender effect on DEX response is suggested.
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PMID:Lack of effect of chronic dextromethorphan on experimental pain tolerance in methadone-maintained patients. 1850 35

Accumulating findings indicate that nucleotides play an important role in microglia through P2 purinoceptors. P2 purinoceptors are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (7 types; P2X(1) - P2X(7)) contain intrinsic pores that open by binding with ATP. P2Y receptors (8 types; P2Y(1, 2, 4, 6, 11, 12, 13 and 14)) are activated by nucleotides and couple to intracellular second-messenger systems through heteromeric G-proteins. Nucleotides are released or leaked from non-excitable cells as well as neurons in physiological and pathophysiological conditions. Microglia express many types of P2 purinoceptors and are known as resident macrophages in the CNS. ATP and other nucleotides work as 'warning molecules' especially through activating microglia in pathophysiological conditions. Microglia play a key role in neuropathic pain, chemotaxis and phagocytosis through nucleotide-evoked activation of P2X(4), P2Y(12) and P2Y(6) receptors, respectively. These findings indicate that extracellular nucleotides are important players in the central stage of microglial function.
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PMID:Purinergic systems in microglia. 1856 92


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