Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiology of nociception involves a complex interaction of peripheral and central nervous system (CNS) structures, extending from the skin, the viscera and the musculoskeletal tissues to the cerebral cortex. The pathophysiology of chronic pain shows alterations of normal physiological pathways, giving rise to hyperalgesia or allodynia. After integration in the spinal cord, nociceptive information is transferred to thalamic structures before it reaches the somatosensory cortex. Each of these levels of the CNS contain modulatory mechanisms. The two most important systems in modulating nociception and antinociception, the N-methyl-D-aspartate (NMDA) and opioid receptor system, show a close distribution pattern in nearly all CNS regions, and activation of NMDA receptors has been found to contribute to the hyperalgesia associated with nerve injury or inflammation. Apart from substance P (SP), the major facilitatory effect in nociception is exerted by glutamate as the natural activator of NMDA receptors. Stimulation of ionotropic NMDA receptors causes intraneuronal elevation of Ca2+ which stimulates nitric oxide synthase (NOS) and the production of nitric oxide (NO). NO as a gaseous molecule diffuses out from the neuron and by action on guanylyl cyclase, NO stimulates in neighboring neurons the formation of cGMP. Depending on the expression of cGMP-controlled ion channels in target neurons, NO may act excitatory or inhibitory. NO has been implicated in the development of hyperexcitability, resulting in hyperalgesia or allodynia, by increasing nociceptive transmitters at their central terminals. Among the three subtypes of opioid receptors, mu- and delta-receptors either inhibit or potentiate NMDA receptor-mediated events, while kappa opioids antagonize NMDA receptor-mediated activity. Recently, CRH has been found to act at all levels of the neuraxis to produce analgesia. Modulation of nociception occurs at all levels of the neuraxis, thus, eliciting the multidimensional experience of pain involving sensory-discriminative, affective-motivational, cognitive and locomotor components.
 ...
PMID:Nociception, pain, and antinociception: current concepts. 1182 34

Glutamate is the fast excitatory transmitter in mammalian brains. It binds to two major classes of glutamate receptors: ionotropic and metabotropic receptors. Ionotropic receptors contain three subtype receptors, including N-methyl-d-aspartate (NMDA) receptors. Activation of NMDA receptors is important for initiating long-lasting changes in synapses. In the forebrain structures that are known to contribute to the formation and storage of information, NMDA receptors have an important role in persistent inflammatory pain by reinforcing glutamate sensory transmission. Mice with enhanced forebrain NMDA receptor function demonstrate selective enhancement of persistent pain and allodynia. Drugs targeting NMDA NR2B subunits in the forebrain could serve as a new class of medicine for controlling persistent pain in humans.
 ...
PMID:Glutamate receptors and persistent pain: targeting forebrain NR2B subunits. 1191 66

Glutamate receptors have been identified on the peripheral terminals of both primary sensory afferents and sympathetic post-ganglionic neurons, and activation of these receptors produces peripheral sensitization and enhances nociception. Adenosine is an endogenous agent that has a regulatory effect on pain. In brain and spinal cord, adenosine release can be promoted by excitatory amino acids. In the present study, we used in vivo microdialysis to determine whether glutamate also can release adenosine in peripheral tissues. Rats were anesthetized with pentobarbital and microdialysis probes were implanted into the subcutaneous tissue of the plantar aspect of the rat hind paw. Subcutaneous injection of glutamate (50 microL, 0.3-100 micromol) evoked a short-lasting adenosine release immediately following drug injection. Co-administration of either the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocipine maleate (MK-801, 1 nmol) or the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline (CNQX, 10 nmol) with glutamate blocked such release, suggesting an involvement of peripheral ionotropic glutamate receptors in this response. Systemic pre-treatment with capsaicin, a neurotoxin selective for unmyelinated sensory afferents, significantly reduced glutamate-evoked peripheral adenosine release, but release was not affected by systemic pre-treatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic nerve efferents. Neither MK-801 nor CNQX blocked 5% formalin-evoked adenosine release, suggesting adenosine release by formalin is not secondary to ionotropic glutamate receptor activation. We conclude that administration of glutamate evokes peripheral adenosine release, and that peripheral ionotropic glutamate receptors on unmyelinated sensory afferents are involved in such release. The released adenosine may provide a negative feedback control on nociception.
 ...
PMID:Intraplantar injection of glutamate evokes peripheral adenosine release in the rat hind paw: involvement of peripheral ionotropic glutamate receptors and capsaicin-sensitive sensory afferents. 1184 63

Vanilloid receptor subunit 1 (VR1) appears to play a critical role in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues. Thus, VR1 antagonists are useful compounds to unravel the contribution of this receptor to pain perception, as well as to induce analgesia. We have used a combinatorial approach to identify new, nonpeptidic channel blockers of VR1. Screening of a library of trimers of N-alkylglycines resulted in the identification of two molecules referred to as DD161515 [N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] and DD191515 [[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] that selectively block VR1 channel activity with micromolar efficacy, rivaling that characteristic of vanilloid-related inhibitors. These compounds appear to be noncompetitive VR1 antagonists that recognize a receptor site distinct from that of capsaicin. Intraperitoneal administration of both trialkylglycines into mice significantly attenuated thermal nociception as measured in the hot plate test. It is noteworthy that these compounds eliminated pain and neurogenic inflammation evoked by intradermal injection of capsaicin into the animal hindpaw, as well as the thermal hyperalgesia induced by tissue irritation with nitrogen mustard. In contrast, responses to mechanical stimuli were not modified by either compound. Modulation of sensory nerve fibers excitability appears to underlie the peptoid analgesic activity. Collectively, these results indicate that blockade of VR1 activity attenuates chemical and thermal nociception and hyperalgesia, supporting the tenet that this ionotropic receptor contributes to chemical and thermal sensitivity and pain perception in vivo. These trialkylglycine-based, noncompetitive VR1 antagonists may likely be developed into analgesics to treat inflammatory pain.
 ...
PMID:Attenuation of thermal nociception and hyperalgesia by VR1 blockers. 1185 30

The recent literature on the antinociceptive action of ionotropic glutamate receptor antagonists is reviewed with special emphasis on their clinical potential. Actually the glutamatergic pathways descending from the brain stem into the spinal cord may generate analgesia. However, physiologically more important is that glutamate and aspartate are apparently the main neurotransmitters along the ascending nociceptive pathways in the spinal cord. Glutamate, aspartate and their receptors can be detected in particularly high concentrations in the dorsal root ganglia and the superficial laminae (I, II) of the spinal cord. In low doses glutamate receptor antagonists only slightly elevate the threshold of the physiological pain sensation. However, they suppress the process of pathological sensitisation i.e. lowering of the pain threshold seen upon excessive or lasting stimulation of C-fibre afferents, a process that takes place during inflammation or other kinds of tissue injury. At electrophysiological level antagonists of both the NMDA- and AMPA/kainate receptors inhibit wind up i.e. lasting activation of the polymodal, second-order sensory neurones in the deeper layers of the dorsal horn. During sensitisation the resting Mg(++) blockade of transmembrane Ca(++) channels is abolished, certain second messenger pathways are activated, the transcription of many genes is enhanced leading to overproduction of glutamate and other excitatory neurotransmitters and expression of Na(+) channels in the primary sensory neurones activated at lower level of depolarisation. This cascade of events leads to increased excitability of the pain pathways. NMDA antagonists are apparently more potent in experimental models of neuropathic pain, whereas AMPA antagonists are more effective in abolition of hyperalgesia seen during experimental inflammation. Clinically, of the previously known NMDA antagonists amantadine, dextromethorphan and ketamine have been tested, the latter extensively. Ketamine has been found quite active in certain cases of neuropathic pain and it reduced the opiate demand when used for postoperative analgesia. However, in other types of clinical pain their efficacy is less convincing. Not being registered there are no clinical data on the AMPA antagonists. There are, however, some investigational new drugs and some novel compounds in the stage of preclinical development which antagonise the AMPA receptors in competitive fashion or allosterically. Of the latter molecules 2,3-benzodiazepines are particularly promising.
 ...
PMID:The role of ionotropic glutamate receptors in nociception with special regard to the AMPA binding sites. 1194 38

Trigeminal afferent neurons express ionotropic P2X receptors for extracellular ATP which are known to be sensitive to low interstitial pH. Both conditions - ATP release and tissue acidosis - may occur in the dura following the ischemia phase of migraine attacks. Aim of this study was to investigate whether and how ATP and protons may cooperate in exciting meningeal afferents. After removal of the cerebral hemispheres hemisected scull cavities of adult Wistar rats were used as organ bath of their own lining, the dura mater. The dura was chemically stimulated and the amounts of immunoreactive calcitonin gene-related peptide (iCGRP) and prostaglandin E(2) (PGE(2)) released into incubation fluid were measured using enzyme immunoassays. Stimulation with ATP (10(-4) and 10(-3)M) augmented iPGE(2) release dose-dependently whereas iCGRP secretion was minimally enhanced only if the dura had previously been depleted of extracellular ATP using hexokinase. Acid buffer solutions (pH 5.9 and 5.4) resulted in pH-dependent increase of iCGRP release but reduced iPGE(2) release. Purines (ATP 10(-3)>UTP 10(-4)M>ATP 10(-4)M) and PGE(2) (10(-5)M) were found to facilitate the proton-induced increase in iCGRP release. The proton-reduction of PGE(2) release was overcome by adding ATP (10(-3)M). S(+)-flurbiprofen (10(-6)M) suppressed both the basal and stimulated iPGE(2) release and prevented the ATP(10(-4)M)-induced facilitation of the proton response. The facilitating effect of ATP was also blocked under suramin, a non-selective P2 antagonist, and under reactive blue, an non-selective P2Y-antagonist, but not under pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid, a P2X-antagonist. The present results provide evidence that ATP has poor, if at all, direct excitatory effects on CGRP-containing trigeminal nerve endings in the isolated dura and its facilitatory action seems to depend on G-protein coupled P2Y receptors and secondary PGE(2) release. The UTP effect and the antagonist profile is indicative for the P2Y(2) receptor subtype.
Pain 2002 Jun
PMID:ATP can enhance the proton-induced CGRP release through P2Y receptors and secondary PGE(2) release in isolated rat dura mater. 1204 22

The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate. The ontogeny of the NMDA receptor, a multiple tetrameric and heteromeric channel complex with at least six known subunits, is controlled by three gene families and varies in developmental profile with species and regional brain area. NMDA receptors play a role in excitatory synaptic transmission, in the activity-dependent synaptic plasticity underlying learning and memory, and in pre- and postnatal CNS development, including brain cell differentiation, axonal growth and degeneration of unused neurons. The results of recent studies suggest that sustained alteration of NMDA receptor activation during critical periods of development may have deleterious effects on normal CNS development and function. Neonatal rats administered the NMDA receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 during the first two weeks of life develop abnormal axonal arborization in the retinal connections to the superior colliculus, interfering with normal visual responses. Results from monkey studies suggest that chronic developmental exposure to high doses of a NMDA antagonist, remacemide, has pronounced and long-lasting effects on learning. Recent findings indicate that if NMDA receptors are blocked during a specific period in neonatal life (first two weeks postnatally in the rat), massive apoptotic neurodegeneration results, due not to excitotoxic overstimulation of neurons but to deprivation of stimulation. These observations require further laboratory evidence and support in order to establish their relevance to drug-induced human neurodevelopmental concerns. It is necessary to investigate the relevance of these findings in other animal species in addition to the rat, most notably, nonhuman primates, where neuronal cytoarchitecture and development are significantly different than the rodent but more like the human.
 ...
PMID:Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity. 1207 5

Two unilateral injections of pH 4.0 saline into the gastrocnemius muscle result in a bilateral decrease in mechanical withdrawal threshold after the second injection. This decrease is significant by 4h and lasts through 1 week. The purpose of this study was to characterize the involvement of both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in the spinal cord dorsal horn in the development and maintenance of mechanical hyperalgesia from repeated intramuscular injections of acidic saline. 2-amino-5-phosphonovaleric acid (AP5) (2-20 nmol, 10 microl, pH 7) or 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX) (1-10 nmol, 10 microl, pH 8-9) was administered intrathecally to the lumbar spinal cord to block NMDA and non-NMDA ionotropic glutamate receptors in the dorsal horn, respectively. Drugs were administered at one of three different time points: (1) prior to the first intramuscular injection of pH 4.0 saline on Day 0, (2) prior to the second intramuscular injection of pH 4.0 saline on Day 5, and (3) 1 week after the second injection. Mechanical withdrawal thresholds were measured with von Frey filaments before, 4h, and 24h after injection 1 and before, 4h, 24h, and 1 week after injection 2. AP5 had no effect on mechanical withdrawal thresholds when administered prior to the first intramuscular injection of pH 4.0 saline. When AP5 was administered before the second intramuscular injection, the bilateral decrease in mechanical withdrawal thresholds was delayed for up to 24h. Intrathecal administration of AP5 1 week after the second intramuscular injection of pH 4.0 saline produced a bilateral increase in mechanical withdrawal thresholds. Blockade of non-NMDA glutamate receptors in the spinal cord dorsal horn prior to either the first or second intramuscular injection of pH 4.0 saline had no effect on the development of mechanical hyperalgesia. However, spinal injection of NBQX 1 week after the second intramuscular injection of pH 4.0 saline resulted in an increase in mechanical withdrawal thresholds when compared to vehicle controls. These data suggest that both NMDA and non-NMDA glutamate receptors are involved in the maintenance of chronic, muscle-induced hyperalgesia.
Pain 2002 Jul
PMID:Effects of NMDA and non-NMDA ionotropic glutamate receptor antagonists on the development and maintenance of hyperalgesia induced by repeated intramuscular injection of acidic saline. 1209 18

Recent electrophysiological, behavioral, and biochemical studies revealed that ATP plays a role in facilitating spinal pain transmission via ionotropic P2X nucleotide receptors, although the involvement of metabotropic P2Y nucleotide receptors remains unclear. In the present study, we examined the effects of i.t. administration of P2Y receptor agonists UTP, UDP, and related compounds on nociception in normal rats and tactile allodynia in a neuropathic pain model. In the paw pressure test using normal rats, i.t. administration of UTP (30 and 100 nmol/rat) and UDP (30 and 100 nmol/rat), but not UMP (100 nmol/rat) or uridine (100 nmol/rat), significantly elevated the mechanical nociceptive thresholds, whereas ATP (30 and 100 nmol/rat) and alpha,beta-methylene-ATP (10 and 30 nmol/rat) lowered them. Similarly, in the tail-flick test, UTP (10, 30, and 100 nmol/rat) and UDP (100 nmol/rat) significantly prolonged the thermal nociceptive latency. In the von Frey filament test on normal rats, UTP (100 nmol/rat) and UDP (100 nmol/rat) produced no allodynia to the tactile stimulus, whereas ATP (100 nmol/rat) induced a significant and long-lasting tactile allodynia. In the neuropathic pain model, in which the sciatic nerves of rats were partially ligated, UTP (30 and 100 nmol/rat) and UDP (30 and 100 nmol/rat) produced significant antiallodynic effects. Furthermore, UTP (100 nmol/rat) and UDP (100 nmol/rat) caused no motor deficit in the inclined plane test. Taken together, these results suggest that the activation of UTP-sensitive P2Y(2) and/or P2Y(4) receptors and the UDP-sensitive P2Y(6) receptor, in contrast to P2X receptors, produces inhibitory effects on spinal pain transmission.
 ...
PMID:Analgesic effects of intrathecal administration of P2Y nucleotide receptor agonists UTP and UDP in normal and neuropathic pain model rats. 1223 34

Extracellular adenosine triphosphate (ATP), acting at P2X ionotropic receptors, is implicated in numerous sensory processes. Exogenous ATP has been shown to be algogenic in both animals and humans. Research focus has been directed towards the P2X(3) receptor, as it is preferentially expressed on nociceptive C-fibers and its implication in pain processing is supported by an altered nociceptive phenotype in P2X(3) knock-out mice. In order to further characterize the role of P2X(3) receptor activation in nociception, we evaluated the effects of continuous intrathecal administration of P2X(3) antisense oligonucleotides for 7 days in the rat. P2X(3) receptor antisense oligonucleotide treatment significantly decreased nociceptive behaviors observed after injection of complete Freund's adjuvant (CFA), formalin or alphabeta-methylene ATP into the rat's hind paw. The anti-hyperalgesic effects of the antisense treatment in the CFA model of inflammatory pain were dose related. Similar effects were observed with two distinct P2X(3) antisense oligonucleotides. These behavioral effects were significantly correlated with a decrease in P2X(3) receptor protein expression in the dorsal root ganglia (DRG). In contrast, a decrease in P2X(3) receptor protein expression in the DRG did not affect nociceptive behavior in the carrageenan model of acute thermal hyperalgesia. P2X(3) receptor antisense oligonucleotide treatment also significantly reduced mechanical allodynia observed after spinal nerve ligation. Overall, the present data demonstrate that activation of P2X(3) receptors contribute to the expression of chronic inflammatory and neuropathic pain states and that relief form these forms of chronic pain might be achieved by selective blockade of P2X(3 )receptor expression or activation.
Pain 2002 Sep
PMID:Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. 1223 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>