Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular levels of amino acids were measured during the development of experimental arthritis in anesthetized monkeys. Levels of glutamate, aspartate, glycine, serine, glutamine, taurine, cysteic acid and asparagine were each measured in consecutive 30 min samples before, during and for several hours after injection of kaolin and carrageenan into the articular capsule of one knee. Samples were obtained via a microdialysis probe placed in the lumbar dorsal horn ipsilateral to the injected knee and assayed using HPLC with fluorescence detection. Glutamate, aspartate, glycine and serine increased transiently following intra-articular injection of inflammatory agents. During this period glutamine levels decreased. A second phase of release then occurred which included more prolonged changes in amino acid levels that were sometimes of greater magnitude than those immediately following the injection. In animals which were later observed to have depletion of SP in the dorsal horn of the inflamed side, taurine levels increased starting after the Glu, Asp and Gly had plateaued at near baseline concentrations. Thus during the first stages of joint inflammation EAAs are released into the dorsal horn, followed by increased levels of IAAs, possibly representing activation of the descending endogenous analgesia system. This phase is followed by a semiacute response consisting in part of increased extracellular levels of SP and Tau. While SP is presumably part of an ascending nociceptive transmission system, Tau could be part of a second system aimed at reducing excessive neural activity including neural transmission resulting in intense maintained pain.
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PMID:Neural changes in acute arthritis in monkeys. IV. Time-course of amino acid release into the lumbar dorsal horn. 163 74

Sharp pain is conducted rapidly by myelinated delta A fibers and diffused pain slowly by nonmyelinated C fibers to pseudobipolar neurons in the posterior ganglion and from there to neurons located in the posterolateral horn of the spinal cord. From here on nociferous impulses are transmitted by excitatory peptides (e.g. substance P) or amino acids (e.g. glutamate, aspartate) through interconnecting neurons of the pain pathways, primarily on the contralateral side, to the brain stem and from there to the sensory cortex, where they are appreciated and acted upon. There are specific inhibitory receptors located on axon terminals, near to the release sites of the excitatory amino acids and peptides. Stimulation of these receptors by their appropriate ligands such as endogenous (e.g. enkephalis, endorphins) or exogenous opioids, clonidine, serotonin, somatostatin inhibits the release of excitatory neurotransmitters and relieves pain. There are at least 3 different opioid receptors, called mu-, kappa- and delta-receptors in the spinal cord. These can be differentiated from one another by their specific affinity toward different endogenous or exogenous opioids and the pure narcotic antagonist, naloxone. It appears that the nociferous impulses transmitted by parallel pathways equipped with different inhibitory receptors have to be integrated to produce pain sensation and partial inhibition of transmission in different pathways or complete inhibition in one of the pathways may relieve pain. In recent years the concept of "selective spinal analgesia" has been applied clinically for the relief of postoperative, obstetrical and chronic pain. At first it was expected that the intrathecal or peridural administration of morphine will produce analgesia without the side effects of systemically administered morphine. It soon became evident, however, that intrathecally and peridurally administered morphine after several hours of delay reaches the fourth ventricle and by stimulating mu-receptors may cause respiratory depression and other undesired effects (e.g. nausea, vomiting, pruritus). Several different approaches are being investigated for the production of selective spinal analgesia without side effects. They include: a. the use of more lipophilic, long-lasting opioids (e.g. lofentanil) which would be almost completely absorbed by the spinal cord and therefore would not reach the medullary centers; b. the development of opioids with specific affinity to kappa- and for delta- and little or no affinity to mu-receptors, primarily responsible for side effects; and c. combining lower doses of opioid agonists with alpha 2-adrenergic agonists (e.g. clonidine) or with somatostatin. It is conceivable that in the not-too-distant future, it will be possible to achieve through these measures, selective spinal analgesia without side effects.
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PMID:Pain control with intrathecally and peridurally administered opioids and other drugs. 168 73

While much evidence implicates substance P (SP), an endogenous neurokinin (NK), as a primary sensory transmitter of acute pain in mammalian spinal cord, its role in continuous (tonic) pain is less clear. Although glutamate is co-localized with SP in dorsal root ganglion neurons, its role in nociceptive processing is uncertain. While antagonists of NKs and excitatory amino acids (EAAs) have been found to be antinociceptive in some acute assays, they have not been tested against tonic pain. We hypothesize that: (1) NKs and EAAs contribute to signaling of tonic chemogenic nociception; and (2) interaction between NK and EAA systems is important in determining the perceived intensity of a continuous noxious stimulus. We therefore evaluated two NK antagonists ([D-Pro2,D-Trp7,9] SP (DPDT-SP, 0.26-6.6 nmoles, non-specific) and [D-Pro4, D-Trp7,9,10,Phe11]-SP(4-11) (DPDTP-octa, 1.6-12.3 nmoles, somewhat NK-1 selective], as well as DL-2-amino-5-phosphonovalerate (DL-AP5, NMDA antagonist, 0.05-1 nmole) and urethane (a kainic acid (KA) antagonist at 2.5 mumoles) for antinociceptive activity in the mouse formalin model. Administered intrathecally (i.t.), DL-AP5 and both NK antagonists were significantly antinociceptive while urethane (2.5 mumoles) and naloxone (2.7 nmoles) were inactive. A50 values for mean % analgesia, nmoles/mouse i.t. (95% CLs) were: DPDT-SP, 1.1 (0.79-1.6); DPDTP-octa, 3.9 (2.4-6.1); DL-AP5, 0.29 (0.16-0.71). The antinociception associated with 1.3 nmoles of DPDT-SP was not reversed by co-administering 2.7 nmoles of naloxone. Co-administration of 0.1 nmoles of DL-AP5 with either 1.3 nmoles of DPDT-SP or 3.3 nmoles of DPDTP-octa did not lead to additive antinociception.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model. 171 Nov 93

Analgesia is an important component of general anesthesia. alpha 2-adrenoceptor agonists such as clonidine and dexmedetomidine are effective analgesics at the spinal level, and furthermore, they reduce the volatile anesthetic requirement. In order to probe a possible spinal-level contribution to general anesthetic-induced analgesia, the effects of dexmedetomidine were tested in an isolated spinal cord preparation. The effects of dexmedetomidine were compared with those of isoflurane, and dexmedetomidine-isoflurane interactions were explored. The test response was a nociceptive-related slow ventral root potential (slow VRP) recorded from the isolated neonatal rat spinal cord in response to electrical stimulation of a dorsal root. At 0.2-1.28 vol%, isoflurane reversibly depressed the slow VRP. At a lower concentration (0.14 vol%), isoflurane increased the slow VRP in three of five preparations. At 1.0-1.28 vol%, isoflurane also depressed the monosynaptic reflex. Recovery on washout usually was to a level greater than control. The N-methyl-D-aspartate (NMDA) receptor antagonist (DL)-2-amino 5-phosphonovalerate (10 microM) prevented the rebound to levels above control on isoflurane washout. The earlier components of the slow VRP were more sensitive to isoflurane than were the later. Dexmedetomidine (0.5-10 nM) depressed the slow VRP and had no effect on the monosynaptic reflex. The slow VRP depends on both substance P and glutamate NMDA-receptor-mediated neurotransmission; isoflurance and dexmedetomidine depressed responses to both substance P and NMDA. Although the two agents depress responses to the same neurotransmitters, there is no evidence that they act at the same cellular site(s). There was no significant interaction between dexmedetomidine and isoflurane. The results suggest that isoflurane exerts marked inhibitory effects on spinal neurotransmission, depressing both substance P and glutamate-mediated pathways. There is a possible biphasic effect on the NMDA receptor. To the extent that nociception depends on these neurotransmitters, isoflurane may be expected to exert profound analgesic effects at the spinal level. By blocking responses to strongly arousing stimuli, these effects may contribute to general anesthesia. Suppression of nociceptive neurotransmission at the spinal level may contribute to dexmedetomidine's anesthetic-sparing properties as well as to analgesia by this agent.
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PMID:Isoflurane and an alpha 2-adrenoceptor agonist suppress nociceptive neurotransmission in neonatal rat spinal cord. 171 80

The present experiment examined descending inhibition of the nociceptive tail-flick reflex produced by microinjection of morphine and glutamate into the periaqueductal gray (PAG) matter and the neurotransmitters mediating the inhibition at the level of the nucleus raphe magnus (NRM). The longlasting opiate analgesia was significantly reduced by microinjection of excitatory amino acid antagonists 1-(p-chlorobenzoyl)-piperazine-2,3-dicarboxylate (PCB, 3.25 mumol) or DL-2-amino-5-phosphono-valerate (APV, 25.38 mumol) into the NRM, whereas the short-lived glutamate analgesia was not. This indicates that although both opiate and non-opiate analgesia may originate in the PAG, the former is relayed through the NRM, whereas the latter is relayed by additional or different nuclei in the medulla. Two observations shed light on the question which receptors mediate the above effect in the NRM. First, PCB blocked morphine analgesia at doses that were 8 times lower than doses of APV that were effective. Second, analgesia produced by injection of glutamate into the NRM was antagonized by PCB (3.25 mumol), whereas APV (25.38 mumol) failed to do so. Together these results indicate that kainate/quisqualate, but not N-methyl-D-aspartate (NMDA), receptors are implicated in the NRM as a relay station in opiate descending inhibition.
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PMID:The role of glutamate in opiate descending inhibition of nociceptive spinal reflexes. 197 28

Microinjection into the midbrain periaqueductal gray (PAG) or lateral reticular formation (LRF) of the neuronal excitant glutamate produces analgesia, and suppresses the responses of a fraction of spinal dorsal horn neurons to noxious heat applied to ventral hind paw skin. Microinjection of morphine into the PAG also produces analgesia, but has been reported to frequently facilitate, as well as to suppress or have no effect, on nociceptive spinal neurons. In anesthetized rats, we tested whether (a) glutamate microinjections into PAG or LRF, and (b) morphine microinjections into PAG, affected the isometric force of hind limb withdrawal elicited by the same noxious heat stimuli on the hind paw as used in single-unit studies of dorsal horn neurons. Glutamate (0.5 M; 0.1-0.5 microliter) microinjected at 9/12 PAG and 8/10 LRF sites suppressed the reflex, and had no effect or facilitated the reflex from the remaining sites. Morphine (5 micrograms in 0.5 microliter) microinjected at each of 10 PAG sites suppressed the reflex in a naloxone-reversible manner. Suppression usually began shortly after morphine, peaked at 20-40 min, and lasted greater than 60 min. The integrated flexion reflex thus appears to be more susceptible to chemical midbrain stimulation under these experimental conditions, compared to previous studies of single dorsal horn neurons.
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PMID:Suppression of a hind limb flexion withdrawal reflex by microinjection of glutamate or morphine into the periaqueductal gray in the rat. 198 May 35

(1) Valproic acid is an anticonvulsant agent widely used in the management of various forms of epilepsy, including absence, myoclonic and tonic-clonic seizures. (2) It also has anticonvulsant potency in a wide variety of animal models of epilepsy. (3) This action is generally thought to be exerted through modulation of the activity of the endogenous inhibitory neurotransmitter, gamma-aminobutyric acid. (4) Evidence that valproic acid interacts with the gamma-aminobutyric acid system is presented. (5) Interactions of valproic acid with other neurotransmitters, i.e. aspartate, glutamate, taurine, serotonin, as well as with cyclic nucleotides and hormones are also considered. (6) Direct effects of valproic acid on excitable membranes and its relationships with analgesia are outlined.
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PMID:Neurophysiological and biochemical changes evoked by valproic acid in the central nervous system. 211 Mar 71

1. In view of the presence of mu, delta and kappa opioid receptors in the spinal dorsal horn and their apparent involvement in behavioural analgesia, the present experiments addressed the action of selective agonists ionophoresed in the vicinity of rat dorsal horn neurones which were located either in lamina I or in laminae III-V. 2. In laminae III-V, kappa agonists (U50488H and dynorphin A) caused a selective inhibition of the nociceptive responses of multireceptive cells, whilst mu and delta agonists [( D-Ala2, MePhe4, Gly-ol]enkephalin and [D-Pen2, D-Pen5]enkephalin respectively) failed to alter either the spontaneous activity or the response to noxious and innocuous cutaneous stimuli and to D,L-homocysteic acid or glutamate. Nocispecific neurones were encountered too rarely in laminae III-V to study their properties. 3. In lamina I, agonists had no effects on either nocispecific or multireceptive neurones. In contrast, the mu agonist [D-Ala2, MePhe4, Gly-ol]enkephalin consistently inhibited nociceptive responses of both multireceptive and nocispecific lamina I cells. The delta agonist [D-Pen2, D-Pen5]enkephalin consistently caused selective inhibition of the nociceptive responses of multireceptive cells but had a mixed profile of action on nocispecific cells. 4. These results suggest that mu, delta and kappa opioid receptors mediate different antinociceptive actions in both laminae III-V and lamina I. The study reveals a distinct physiological role for delta receptors in modulating nociceptive inputs to lamina I neurones. In contrast to mu and kappa receptor actions, delta receptors heterogeneously influence subpopulations of neurones.
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PMID:Distinct antinociceptive actions mediated by different opioid receptors in the region of lamina I and laminae III-V of the dorsal horn of the rat. 217 38

The present work reviews neurochemical, physiological and behavioral data recorded from the attacked mouse and integrates them into a model of coping mechanisms during social conflict. More specifically, the possible relationships between systems of pain, memory and defense are presented, with special emphasis on the role of endogenous opioid peptides (EOPs). In recipients of attack, decreased beta-endorphin-like immunoreactivity and changes in opiate and benzodiazepine binding characteristics are found in structures of the brain defensive system. EOPs mediate the social conflict-induced increase of dopamine synthesis in the periaqueductal grey and frontal cortex. Social conflict analgesia in attacked mice is under the control of central opioid and nonopioid (e.g., benzodiazepine, glutamate) mechanisms, and is modified by experience (e.g., long-term analgesic reaction; tolerance). EOPs and pain-inhibitory mechanisms participate in the organization of behavioral defense, recuperative behavior and the memory of attack experience. The data are considered in relation to the perceptual-defensive-recuperative model of fear and pain, forwarded by Bolles and Fanselow.
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PMID:An ethological model for the study of activation and interaction of pain, memory and defensive systems in the attacked mouse. Role of endogenous opioids. 228 85

Extracellular single-unit recordings were made from dorsal horn neurones in the lumbar spinal cord of cats which were anaesthetized or were anaemically decerebrated. Each neurone was classified functionally as wide dynamic range (WDR), non-nociceptive, nociceptive specific or proprioceptive. Vibration was then applied to the hind limb using a feedback-controlled mechanical stimulator. WDR neurones had 3 distinct types of response to vibration (80 Hz: 0.3-1.0 mm): excitation, depression and a biphasic response consisting of excitation followed by depression. The type of response depended upon the location of the stimulator probe. With the stimulator probe placed inside that part of the receptive field from which low intensity, non-vibrational cutaneous stimuli elicited excitation, 35 neurones were excited by the vibratory stimulation, none was depressed and 4 showed the biphasic response. On the other hand, when the probe was positioned outside the receptive field for low intensity stimuli, 7 WDR neurones were excited, 164 showed depression or the biphasic response and 7 were unaffected. On-going activity and activity evoked by iontophoretic application of glutamate were decreased during the depressant response and during the depressant phase of the biphasic response. In terms of non-nociceptive neurones, all (n = 30) were excited by vibration; depressant or biphasic responses were not observed. Excitation was elicited by placing the probe either inside or outside the receptive field for non-vibrational stimuli. All nociceptive specific neurones (n = 3) were depressed by vibration regardless of the position of the stimulus. All proprioceptive neurones (n = 12) were excited by vibration. The predominantly depressant effect of vibration on nociceptive neurones vs. the predominantly excitatory effect on non-nociceptive neurones prompts us to suggest that the increase in pain threshold and the clinical analgesia elicited by vibration may be mediated at the spinal level by a decrease in the rate of firing of nociceptive neurones and/or by excitation of non-nociceptive neurones.
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PMID:Differential responses of nociceptive vs. non-nociceptive spinal dorsal horn neurones to cutaneously applied vibration in the cat. 232 96


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