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)

Recent evidence suggests that spinal cord glia can contribute to enhanced nociceptive responses. However, the signals that cause glial activation are unknown. Fractalkine (CX3C ligand-1; CX3CL1) is a unique chemokine expressed on the extracellular surface of spinal neurons and spinal sensory afferents. In the dorsal spinal cord, fractalkine receptors are primarily expressed by microglia. As fractalkine can be released from neurons upon strong activation, it has previously been suggested to be a neuron-to-glial signal that induces glial activation. The present series of experiments provide an initial investigation of the spinal pain modulatory effects of fractalkine. Intrathecal fractalkine produced dose-dependent mechanical allodynia and thermal hyperalgesia. In addition, a single injection of fractalkine receptor antagonist (neutralizing antibody against rat CX3C receptor-1; CX3CR1) delayed the development of mechanical allodynia and/or thermal hyperalgesia in two neuropathic pain models: chronic constriction injury (CCI) and sciatic inflammatory neuropathy. Intriguingly, anti-CX3CR1 reduced nociceptive responses when administered 5-7 days after CCI, suggesting that prolonged release of fractalkine may contribute to the maintenance of neuropathic pain. Taken together, these initial investigations of spinal fractalkine effects suggest that exogenous and endogenous fractalkine are involved in spinal sensitization, including that induced by peripheral neuropathy.
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PMID:Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. 1552 71

Opioid-containing leukocytes can counteract inflammatory hyperalgesia. Under stress or after local injection of corticotropin releasing factor (CRF), opioid peptides are released from leukocytes, bind to opioid receptors on peripheral sensory neurons and mediate antinociception. Since polymorphonuclear cells (PMN) are the predominant opioid-containing leukocyte subpopulation in early inflammation, we hypothesized that PMN and their recruitment by chemokines are important for peripheral opioid-mediated antinociception at this stage. Rats were intraplantarly injected with complete Freund's adjuvant (CFA). Using flow cytometry, immunohistochemistry, and ELISA, leukocyte subpopulations, chemokine receptor (CXCR2) expression on opioid-containing leukocytes and the CXCR2 ligands keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant-2 (CINC-2) were quantified. Paw pressure threshold (PPT) was determined before and after intraplantar and subcutaneous injection of CRF with or without naloxone. PMN depletion was achieved by intravenous injection of an antiserum. Chemokines were blocked by intraplantar injection of anti-MIP-2 and/or anti-KC antiserum. We found that at 2 h post CFA (i) intraplantar but not subcutaneous injection of CRF produced dose-dependent and naloxone-reversible antinociception (P<0.05, ANOVA). (ii) Opioid-containing leukocytes in the paw and CRF-induced antinociception were reduced after PMN depletion (P<0.05, t-test). (iii) Opioid-containing leukocytes mostly expressed CXCR2. MIP-2 and KC, but not CINC-2 were detectable in inflamed but not in noninflamed tissue (P<0.05, ANOVA). (iv) Combined but not single blockade of MIP-2 and KC reduced the number of opioid-containing leukocytes and peripheral opioid-mediated antinociception (P<0.05, t-test; P>0.05, ANOVA). In summary, in early inflammation peripheral opioid-mediated antinociception is critically dependent on PMN and their recruitment by CXCR2 chemokines.
Pain 2004 Dec
PMID:Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells. 1556 77

One subset of the G-protein coupled receptor (GPCR) superfamily is that which is activated by a peptide carrying an obligatory positively charged residue (GPCR-PA(+)). This subclass is exemplified by receptors for melanocortins, GnRH, galanin, MCH, orexin, and some chemokine receptors variously involved in eating disorders, reproductive disorders, pain, narcolepsy, obesity, and inflammation. Using the methods described in this study, a region of chemical property space enriched in GPCR ligands was identified. This information was used to design and synthesize a "test" library of 2025 single, pure compounds to sample portions of this property space associated with GPCR-PA(+) ligands. The library was evaluated by high-throughput screening against three different receptors, rMCH, hMC4, and hGnRH, and found to be highly enriched in active ligands (4.5-61-fold) compared to a control set of 2024 randomly selected compounds. In addition, the analysis suggested that about 7000 compounds will be necessary to complete the sampling of this GPCR-PA(+) ligand-rich region and to better define its borders.
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PMID:A screening library for peptide activated G-protein coupled receptors. 1. The test set. 1561 35

Neuropathic pain therapy remains enormously challenging despite the increases in knowledge of pain etiology and mechanisms drawn from animal studies. Mechanism-based discovery underlies key approaches toward reduction of peripheral and central hyperexcitability. These include a number of poorly validated molecular targets, such as ion channels, G-protein coupled receptors, purinergic receptors, and chemokine receptors, as well as downstream regulators of protein phosphorylation. Improvement in translating these approaches into the development of drugs for use in the pain clinic remains a significant but surmountable challenge.
J Orofac Pain 2004
PMID:Future pharmacologic management of neuropathic pain. 1563 24

Pain, a critical component of host defense, is one hallmark of the inflammatory response. We therefore hypothesized that pain might be exacerbated by proinflammatory chemokines. To test this hypothesis, CCR1 was cotransfected into human embryonic kidney (HEK)293 cells together with transient receptor potential vanilloid 1 (TRPV1), a cation channel required for certain types of thermal hyperalgesia. In these cells, capsaicin and anandamide induced Ca(2+) influx mediated by TRPV1. When CCR1:TRPV1/HEK293 cells were pretreated with CCL3, the sensitivity of TRPV1, as indicated by the Ca(2+) influx, was increased approximately 3-fold. RT-PCR analysis showed that a spectrum of chemokine and cytokine receptors is expressed in rat dorsal root ganglia (DRG). Immunohistochemical staining of DRG showed that CCR1 is coexpressed with TRPV1 in >85% of small-diameter neurons. CCR1 on DRG neurons was functional, as demonstrated by CCL3-induced Ca(2+) ion influx and PKC activation. Pretreatment with CCL3 enhanced the response of DRG neurons to capsaicin or anandamide. This sensitization was inhibited by pertussis toxin, U73122, or chelerythrine chloride, inhibitors of Gi-protein, phospholipase C, and protein kinase C, respectively. Intraplantar injection of mice with CCL3 decreased their hot-plate response latency. That a proinflammatory chemokine, by interacting with its receptor on small-diameter neurons, sensitizes TRPV1 reveals a previously undescribed mechanism of receptor cross-sensitization that may contribute to hyperalgesia during inflammation.
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PMID:A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. 1576 7

Neuronal hyperexcitability in both injured and adjacent uninjured neurons is associated with states of chronic injury and pain and is likely subject to neuroinflammatory processes. Chronic inflammatory responses are largely orchestrated by chemokines. One chemokine, monocyte chemoattractant protein-1 (MCP-1), in the presence of its cognate receptor, the beta chemokine receptor 2 (CCR2), produces neural activity in dissociated neuronal cultures of neonatal dorsal root ganglion (DRG) neurons. Using a neuropathic pain model, chronic compression of the DRG (CCD), we compared anatomically separate populations of noncompressed lumbar DRG (L3/L6) with compressed lumbar DRG (L4/L5) for changes in the gene expression of CCR2. In situ hybridization revealed that CCR2 mRNA was up-regulated in neurons and nonneuronal cells present in both compressed L4/L5 and ipsilateral noncompressed L3/L6 DRGs at postoperative day 5 (POD5). The total percentages of compressed and noncompressed neurons exhibiting CCR2 mRNA transcripts in L3, L5, and L6 DRG were 33 +/- 3.5%, 49 +/- 6.2%, and 41 +/- 5.6%, respectively, and included cell bodies of small, medium, and large size. In addition, the preferred CCR2 ligand, MCP-1, was up-regulated by POD5 in both compressed L4/L5 and noncompressed L3/L6 DRG neurons. Application of MCP-1 to the cell bodies of the intact formerly compressed DRG in vitro produced potent excitatory effects not observed in control ganglia. MCP-1/CCR2 signaling is directly involved with a chronic compression injury and may contribute to associated neuronal hyperexcitability and neuropathic pain.
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PMID:Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. 1617 30

Chemokine receptors, a family of Gi protein-coupled receptors responsible for cell migration, are widely expressed by cells of immune and nervous systems. Activation of receptors on the surface of leukocytes, such as opioid, vasoactive intestinal peptide, or adenosine receptors, often has inhibitory effects on chemokine receptors by a mechanism termed heterologous desensitization, resulting in suppression of immune responses. Conversely, activation of chemokine receptors also induces heterologous desensitization of mu-opioid receptors (MOR), a class of key analgesic receptors on neurons. Furthermore, prior exposure of neuronal cells to chemokine treatment enhances the sensitivity of transient receptor potential vanilloid 1 (TRPV1), a heat- and ligand-gated calcium channel, which is critical for sensing of pain. Consequently, during inflammation, activation of chemokine receptors on neurons contributes to hyperalgesia by inhibiting MOR and concomitantly sensitizing TRPV1 via Gi protein-mediated signaling pathways. These observations suggest that the crosstalk between chemokine receptors and neuropeptide membrane receptors serves as a bridge between the immune and nervous systems.
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PMID:Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems. 1620 35

Fractalkine is a chemokine that is tethered to the extracellular surface of neurons. Fractalkine can be released, forming a diffusible signal. Spinal fractalkine (CX3CL1) is expressed by sensory afferents and intrinsic neurons, whereas its receptor (CX3CR1) is predominantly expressed by microglia. Pain enhancement occurs in response both to intrathecally administered fractalkine and to spinal fractalkine endogenously released by peripheral neuropathy. The present experiments examine whether fractalkine-induced pain enhancement is altered by a microglial inhibitor (minocycline) and/or by antagonists/inhibitors of three putative glial products implicated in pain enhancement: interleukin-1 (IL1), interleukin-6 (IL6) and nitric oxide (NO). In addition, it extends a prior study that demonstrated that intrathecal fractalkine-induced mechanical allodynia is blocked by a neutralizing antibody to the rat fractalkine receptor, CX3CR1. Here, intrathecal anti-CX3CR1 also blocked fractalkine-induced thermal hyperalgesia. Furthermore, blockade of microglial activation with minocycline prevented both fractalkine-induced mechanical allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). Microglial activation appears to lead to the release of IL1, given that pretreatment with IL1 receptor antagonist blocked both fractalkine-induced mechanical allodynia and thermal hyperalgesia. IL1 is not the only proinflammatory cytokine implicated, as a neutralizing antibody to rat IL6 also blocked fractalkine-induced pain facilitation. Lastly, NO appears to be importantly involved, as l-NAME, a broad-spectrum NO synthase inhibitor, also blocked fractalkine-induced effects. Taken together, these data support that neuronally released fractalkine enhances pain via activation of spinal cord glia. Thus, fractalkine may be a neuron-to-glia signal triggering pain facilitation.
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PMID:An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. 1632 11

Human immunodeficiency virus (HIV)-wasting syndrome might be facilitated by the HIVgp120 affecting the immunological system. We studied the effect (subchronic administration: 5 days) of HIVgp120, and a few immune-response mediators: regulated upon activation normal T-cell expressed and presumably secreted (RANTES), stromal derived factor-1alpha (SDF-1alpha), macrophage-derived chemokine (MDC), and their combination, on food and water intake in rats, motor control and pain perception. Eighty male adult Wistar rats received an intracerebroventricular (icv) administration of: vehicle 5 microl/day or 0.92 nmol daily of HIVgp120IIIB, RANTES, SDF-1alpha, or MDC, and the combination of RANTES+HIVgp120IIIB, SDF-1alpha+HIVgp120IIIB, or MDC+HIVgp120IIIB. Food and water intake was measured every day during administration, and 24 and 48 h after the last administration. Rats were also weighed the first and the last day of experiment in order to detect the impact of these treatments in the body weight. HIVgp120IIIB significantly decreased food and water intake. These rats gain less weight than the control (vehicle) and chemokines-treated subjects with exception of those treated with SDF-1alpha that also gain less weight. In addition, HIVgp120 deteriorated motor control. HIVgp120IIIB effects on food and water intake, and motor control were prevented by these chemokines. HIVgp120+RANTES, HIVgp120+SDF-1alpha, and SDF-1alpha alone induced hyperalgesia. Results suggest an interaction between HIVgp120 and the chemokine system to generate the HIV-wasting syndrome, the motor abnormalities and changes in pain perception.
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PMID:RANTES, MDC and SDF-1alpha, prevent the HIVgp120-induced food and water intake decrease in rats. 1634 73

Polymorphonuclear cells (PMN) are recruited in early inflammation and are believed to contribute to inflammatory pain. However, studies demonstrating a hyperalgesic role of PMN did not examine selective PMN recruitment or did not document effective PMN recruitment. We hypothesized that hyperalgesia does not develop after chemokine-induced PMN selective recruitment and is independent of PMN infiltration in complete Freund's adjuvant (CFA)-induced, local inflammation. PMN were recruited by intraplantar injection of CXC chemokine ligand 1 (CXCL1; keratinocyte-derived chemokine), CXCL2/3 (macrophage inflammatory protein-2), or CFA, with or without preceding systemic PMN depletion. Chemokine inoculation resulted in dose (0-30 microg)- and time (0-12 h)-dependent, selective recruitment of PMN as quantified by flow cytometry. CXCL2/3, but not CXCL1, was less effective at high doses, probably as a result of significant down-regulation of CXC chemokine receptor 2 expression on blood PMN. Neither chemokine caused mechanical or thermal hyperalgesia as determined by the Randall-Selitto and Hargreaves test, respectively, despite comparable expression of activation markers (i.e., CD11b, CD18, and L-selectin) on infiltrating PMN. In contrast, CFA injection induced hyperalgesia, independent of PMN recruitment. c-Fos mRNA and immunoreactivity in the spinal cord were increased significantly after inoculation of CFA-independent of PMN-migration but not of CXCL2/3. Measurement of potential hyperalgesic mediators showed that hyperalgesia correlated with local prostaglandin E2 (PGE2) but not with interleukin-1beta production. In summary, hyperalgesia, local PGE2 production, and spinal c-Fos expression occur after CFA-induced inflammation but not after CXCL1- or CXCL2/3-induced, selective PMN recruitment. Thus, PMN seem to be less important in inflammatory hyperalgesia than previously thought.
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PMID:Selective local PMN recruitment by CXCL1 or CXCL2/3 injection does not cause inflammatory pain. 1689 80


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