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)

Important breakthroughs in the understanding regeneration failure in an injured CNS have been made by studies of primary afferent neurons. Dorsal rhizotomy has provided an experimental model of brachial plexus (BP) avulsion. This is an injury in which the central branches of primary afferents are disrupted at their point of entry into the spinal cord, bringing motor and sensory dysfunction to the upper limbs. In the present work, the central axonal organization of primary afferents was examined in control (without lesion) adult Wistar rats and in rats subjected to a C3-T3 rhizotomy. Specific sensory axon subtypes were recognized by application of antibodies to the calcitonin gene-related peptide (CGRP), the P2X3 purinoreceptor, the low-affinity p75-neurotrophin receptor and the retrograde tracer cholera toxin subunit beta (TCbeta). Other subtypes weres labeled with the lectin Griffonia simplicifolia 1B4. Using immunohistochemistry and high resolution light microscopy, brachial plexus rhizotomy in adult rats has proven a reliable model for several neural deficits in humans. This lesion produced different degrees of terminal degeneration in the several types of primary afferents which define sub-populations of sensitive neurons. Between the C6 and C8 levels of the spinal cord,, deafferentation was partial for peptidergic GCRP-positive fibers, in contrast with elimination of non peptidergic and myelinated fibers. Dorsal rhizotomy has provided an adequate experimental model to study sensory alterations such as acute pain and allodynia as well as factors that affect regeneration into the CNS., Therefore, the differential deafferentation response must be considered inr the evaluation of therapies for nociception (pain) and regeneration for brachial plexus avulsion. The anatomical diffierences among the primary afferent subtypes also affect their roles in normal and damaged conditions.
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PMID:Degeneration of primary afferent terminals following brachial plexus extensive avulsion injury in rats. 1549 98

The effect of A-317491 (5-([(3-Phenoxybenzyl)[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl)-1,2,4-benzenetricarboxylic acid), a recently described selective P2X3 and P2X(2/3) receptor antagonist, on inflammatory mechanical hyperalgesia was examined. In the rat Freund's complete adjuvant model of inflammatory pain, s.c. administration of A-317491 dose-dependently reversed mechanical hyperalgesia. Maximum percent reversal (72%) was seen 3 h after administration at 10 mg/kg. Substantial plasma concentrations were measured for A-317491 after s.c. dosing 3, 10 and 30 mg/kg. However, the brain-to-plasma concentration ratio, determined 1 h after a 10 mg/kg s.c. dose, indicated limited penetration of A-317491 into the central nervous system. As revealed by neural activity recorded from single C-fiber nociceptive afferent in a Freund's complete adjuvant-inflamed rat skin-nerve preparation, topical application of A-317491 completely blocked afferent activation and mechanical sensitization induced by alpha,beta-methylene ATP, a P2X agonist. These results suggest that A-317491 is a peripherally acting P2X blocker. Its efficacy demonstrates the importance of peripheral P2X3/P2X(2/3) receptors in mediating ATP-associated mechanical hyperalgesia following inflammation, confirming previous suggestions of a significant role for P2X(2/3).
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PMID:A-317491, a selective P2X3/P2X2/3 receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at peripheral receptors in rats. 1550 20

Evidence is accumulating which supports a role for ATP in the initiation of pain by acting on P2X receptors expressed on nociceptive afferent nerve terminals. To investigate whether these receptors play a role in temporomandibular (TMJ) pain, we studied the presence of functional P2X receptors in rat TMJ by examining the nociceptive behavioral response to the application of the selective P2X receptor agonist alpha,beta-methylene ATP (alpha,beta-meATP) into the TMJ region of rat. The involvement of endogenous ATP in the development of TMJ inflammatory hyperalgesia was also determined by evaluating the effect of the general P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on carrageenan-induced TMJ inflammatory hyperalgesia. Application of alpha,beta-meATP into the TMJ region of rats produced significant nociceptive responses that were significantly reduced by the co-application of lidocaine N-ethyl bromide quaternary salt, QX-314, (2%) or of the P2 receptor antagonist PPADS. Co-application of PPADS with carrageenan into the TMJ significantly reduced inflammatory hyperalgesia. The results indicate that functional P2X receptors are present in the TMJ and suggest that endogenous ATP may play a role in TMJ inflammatory pain mechanisms possibly by acting primarily in these receptors.
Eur J Pain 2005 Feb
PMID:Evidence for the involvement of endogenous ATP and P2X receptors in TMJ pain. 1562 79

Some vagal afferent nerves are thought to mediate autonomic responses evoked by noxious oesophageal stimuli and participate in the perception of pain originating in the oesophagus. However, the vagal nociceptive nerve phenotypes implicated in this function have yet to be identified. In this study, nociceptive fibres were defined by the capacity to discriminate noxious mechanical stimuli (wide range of oesophageal distension with pressure up to 100 mmHg) and detect noxious chemical stimuli (the activators of capsaicin receptor TRPV1). Using immunohistochemical techniques with retrogradely labelled oesophagus-specific neurones and performing extracellular recordings from the isolated vagally innervated oesophagus, we show that in the guinea-pig, the vagus nerves supply the oesophagus with a large population of nociceptive-like afferent nerve fibres. Vagal nociceptive-like fibres in the guinea-pig oesophagus are derived from two embryonically distinct sources: neurones situated in the nodose vagal ganglia and neurones situated in the jugular vagal ganglia. Nodose (placode-derived) nociceptive-like fibres are exclusively C-fibres sensitive to a P2X receptors agonist and rarely express the neuropeptide substance P. In contrast, jugular (neural crest-derived) nociceptive-like fibres include both A-fibres and C-fibres, are insensitive to P2X receptors agonist and mostly express substance P. The non-nociceptive vagal tension mechanoreceptors are distinguished from nociceptors by their saturable response to oesophageal distension and by the lack of TRPV1. These tension mechanoreceptors are exclusively A-fibres arising from the nodose ganglion. We conclude that the vagus nerves supply the guinea-pig oesophagus with nociceptors in addition to tension mechanoreceptors. The vagal nociceptive-like fibres in the oesophagus comprise two distinct subtypes dictated by the ganglionic location of their cell bodies.
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PMID:Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus. 1564 87

Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Such pain can be experienced after nerve injury or as part of diseases that affect peripheral nerve function, such as diabetes and AIDS; it can also be a component of pain in other conditions, such as cancer. Following peripheral nerve injury, microglia in the spinal cord become activated. Recent evidence indicates that activated microglia are key cellular intermediaries in the pathogenesis of nerve injury-induced pain hypersensitivity because P2X(4) purinoceptors and p38 mitogen-activated protein kinase, which are present in activated microglia, are required molecular mediators. It is important to establish how these molecules are activated in spinal microglia following nerve injury and how they cause signaling to neurons in the dorsal horn pain transmission network. Answers to these questions could lead to new strategies that assist in the diagnosis and management of neuropathic pain--strategies not previously anticipated by a neuron-centric view of pain plasticity in the dorsal horn.
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PMID:Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. 1566 33

Purines, such as adenosine and ATP, are endogenous ligands involved in modulating pain transmission and pain hypersensitivity by acting on P1 and P2 purinoceptors, respectively, at sites both in peripheral tissues and in the central nervous system. For P1 (adenosine) receptors, clinical studies in humans, as well as experimental animal studies, have demonstrated that activation of the A1 subtype reduces both inflammatory and neuropathic types of chronic pain. For P2 receptors, there is a growing body of evidence indicating that multiple receptor subtypes are differentially involved in pain processing. The most well-known of the P2 receptors is the P2X3 subtype, which is found in primary sensory neurons. Inhibition of P2X3 receptors is effective in reducing pain behaviors in animal models of chronic inflammatory and neuropathic pain. Recently, the P2X, subtype has been implicated in nerve-injury-induced pain hypersensitivity. There is also emerging evidence for roles for P2Y, and P2Y2 receptors, subtypes of G protein-coupled P2 receptors, in pain hypersensitivity. Thus, multiple subtypes of purinoceptors are potential molecular targets for development of new pharmacological agents for the treatment of pain.
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PMID:Purines and pain mechanisms: recent developments. 1567 5

The rat L5/6 facet joint, from which low-back pain can originate, is multisegmentally innervated from the L1 to L5 dorsal root ganglions (DRGs). Sensory fibers from the L1 and L2 DRGs are reported to non-segmentally innervate the paravertebral sympathetic trunks, whilst those from the L3 to L5 DRGs segmentally innervate the L5/6 facet joint. In the current study, characteristics of sensory DRG neurons innervating the L5/6 facet joint were investigated in rats, using a retrograde neurotransport method, lectin affinity- and immuno-histochemistry. We used four markers: (1) calcitonin gene-related peptide (CGRP) as a marker of small peptide containing neurons, (2) the glycoprotein binding the isolectin from Griffonia simplicifolia (IB4) or (3 the purinergic P2X(3) receptor for small, non-peptide containing neurons, and (4) neurofilament 200 (NF200) for small and large myelinated fibers. IB4-binding and CGRP and P2X(3) receptor containing neurons are typically involved in pain sensation, whereas NF200 is associated with pain and proprioception. Neurons innervating the L5/6 facet joints, retrogradely-labeled with fluoro-gold (FG), were distributed throughout DRGs from L1 to L5. Of FG-labeled neurons, the ratios of NF200 immunoreactive (IR) neurons and CGRP-IR neurons were 37% and 35% respectively. The ratio of IB4-binding and P2X(3) receptor-IR neurons was 10%, significantly less than the ratio of CGRP-IR neurons to FG-labeled neurons. The ratios of IB4-binding and P2X(3) receptor-IR neurons were significantly higher, and that of CGRP-IR neurons was significantly less in L1 and L2 DRGs than those in L3, L4 or L5 DRGs. Under physiological conditions in rats, DRG neurons transmit several types of sensations, such as proprioception or nociception of the facet joint. Most neurons transmitting pain are CGRP-IR peptide-containing neurons. They may have a more significant role in pain sensation in the facets via peptidergic DRG neurons.
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PMID:Characteristics of sensory DRG neurons innervating the lumbar facet joints in rats. 1569 Feb 12

Pathological pain is often associated with changed sympathetic nerve activities. It is known that sympathetic nerve endings release ATP as a co-transmitter of norepinephrine, but the effect of this ATP on the nociceptive system has not been properly studied in that the concentration range used in the previous studies was much higher than is expected in the surroundings of nociceptor terminals. We examined the effects of ATP, especially at low concentration (10(-5) M or less), on C-fiber polymodal receptor (CPR) activity using a rat skin-nerve preparation in vitro. We found for the first time that ATP inhibited the heat response of CPRs at low concentration (10(-5) M), but facilitated it at high concentration (10(-3) M). The former effect was mimicked by a P2X3 agonist, alpha,beta-methylene ATP, at 10(-5) M, while the latter was mimicked by 2-methylthio ADP (a P2Y1 agonist) or UTP (a P2Y2 agonist) at 10(-3) M, suggesting that the former is mediated by P2X receptors and the latter by P2Y receptors. After repetitive heat stimuli, ATP-induced CPR excitation was increased (10(-5) to 10(-3) M), but none of the purinergic agonists induced CPR excitation in a magnitude comparable to that by ATP. Possible mechanisms for these effects were discussed.
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PMID:Inhibitory, facilitatory, and excitatory effects of ATP and purinergic receptor agonists on the activity of rat cutaneous nociceptors in vitro. 1574 Aug 3

The P2X(7) purinoceptor is a ligand-gated cation channel, expressed predominantly by cells of immune origin, with a unique phenotype which includes release of biologically active inflammatory cytokine, interleukin (IL)-1beta following activation, and unique ion channel biophysics observed only in this receptor family. Here we demonstrate that in mice lacking this receptor, inflammatory (in an adjuvant-induced model) and neuropathic (in a partial nerve ligation model) hypersensitivity is completely absent to both mechanical and thermal stimuli, whilst normal nociceptive processing is preserved. The knockout animals were unimpaired in their ability to produce mRNA for pro-IL-1beta, and cytometric analysis of paw and systemic cytokines from knockout and wild-type animals following adjuvant insult suggests a selective effect of the gene deletion on release of IL-1beta and IL-10, with systemic reductions in adjuvant-induced increases in IL-6 and MCP-1. In addition, we show that this receptor is upregulated in human dorsal root ganglia and injured nerves obtained from chronic neuropathic pain patients. We hypothesise that the P2X(7) receptor, via regulation of mature IL-1beta production, plays a common upstream transductional role in the development of pain of neuropathic and inflammatory origin. Drugs which block this target may have the potential to deliver broad-spectrum analgesia.
Pain 2005 Apr
PMID:Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. 1577 64

Tetramethylpyrazine (TMP) is one of the alkaloids contained in Ligustrazine which has been used in traditional Chinese medicine as an analgesic for injury and dysmenorrhea. ATP can elicit the sensation of pain. This study observed the effects of TMP on ATP-activated current (IATP) in rat DRG neurons. TMP (0.1-1 mM) concentration-dependently inhibited ATP (100 microM)-activated current in rat DRG neurons. The inhibitory time of ATP (100 microM)-activated current appeared at 15 s after preapplication of TMP and reached its peak at about 45 s. The dose-response curves for IATP in the absence and presence of 1 mM TMP showed that TMP (1 mM) shifted the concentration-response curve of IATP downward markedly and the two EC50 values were very close (75 vs. 82 microM), while the threshold value remained unchanged. Therefore, the inhibitory effect of TMP on IATP may be noncompetitive. TMP did not alter the reversal potential (0 mV) of ATP-activated current, indicating that the site of TMP action is on or near the exterior surface of channel protein and not within the channel pore. Externally applied TMP (1 mM) increases the inhibitory effect of chelerythrine (PKC inhibitor) contained in pipette solution on IATP. The site of TMP action may be the binding of TMP to an allosteric site on the large extracellular region of ATP receptor-ion channel complex (P2X receptors) or PKC site of the N-terminus of P2X receptors. The mechanism of TMP action may be the allosteric regulation via acting on the large extracellular region of ATP receptor-ion channel complex (P2X receptors) and promoting the phosphorylation of PKC site of the N-terminus of P2X receptors.
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PMID:Tetramethylpyrazine inhibits ATP-activated currents in rat dorsal root ganglion neurons. 1580 30


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