Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0184567 (acute pain)
 3,962 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sensitization of the responses of dorsal horn neurons to mechanical stimulation may play a role in the generation of hyperalgesia. Intradermal injection of capsaicin (CAP) provides a model of experimental hyperalgesia that possesses a component of allodynia. This hyperalgesia is produced by chemical stimulation of C-fibers, leading to sensitization of dorsal horn neurons, including spinothalamic tract (STT) cells. The changes in the physiological responses of STT neurons following intradermal CAP in monkeys parallel the acute pain and hyperalgesia produced by intradermal CAP in humans. The present study addresses the role that excitatory amino acids (EAAs) may play in the sensitization of STT neurons by intradermal CAP. Our results show that the background discharge rate and the responses of STT cells to mechanical stimulation increase following intradermal CAP. In addition, the responses of the sensitized cells to one or more iontophoretically released EAA agonists, including NMDA, glutamate, aspartate, kainate, DL-alpha-amino-3-hydroxy-5-methyl-isoxazoleproprionic acid, and/or quisqualate, increase following intradermal CAP. It is proposed that an increase in the responses of STT neurons to EAAs contributes to the hyperalgesia produced by this noxious chemical stimulus.
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PMID:Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey. 154 44

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

The present study had been made to study the distribution and synaptic characteristics of primary afferent C fibers and the normal chemical architecture of some neurotransmitters in spinal dorsal horn. The changes of the neurotransmitters with acute nociceptive stimulation were measured quantitatively. We demonstrated the synaptic relationships among primary afferent C fibers, inhibitory interneurons and nociceptive dorsal horn neurons and discussed their function in nociceptive transmission and modulation. These results provide evidence that acute pain evolved co-release of substance P and glutamate from C-fiber terminals may constitute a driving force for secondary activation of ascending projection neurons or of internal GABAergic antinoceciptive system directly via their receptors in the dorsal horn of the spinal cord.
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PMID:[Chemical anatomy of the nociceptive transmission and modulation in the spinal dorsal horn]. 977 83

Lamotrigine, a sodium channel blocker that selectively inhibits the neuronal release of glutamate, has been shown to produce analgesia in acute and chronic pain models in rats without causing noticeable sedation. After oral administration it also reduces pain scores, as assessed by the cold pain test, in volunteers. The purpose of this study was to determine the analgesic effect of lamotrigine given by mouth to healthy volunteers as evidenced by alterations in chemo-somatosensory evoked potentials. The following factors were measured: latency to N1 and P100 peak (ms); amplitude between the N1 and P100 peak (microV); visual analogue pain intensity scores. A double-blind, randomised and crossover design was used in which 12 volunteers received either placebo or lamotrigine 300 mg on separate occasions as determined by the randomisation schedule. Volunteers were tested before and 2 h after the treatment. The plasma lamotrigine concentration was measured immediately after the end of the experimental sessions. Lamotrigine produced a significantly higher latency to P100 values at 2 h postdrug than placebo (p < 0.05) but had no significant effects on the other factors. Although plasma concentrations were similar to those observed in the cold pain test, we conclude that lamotrigine 300 mg by mouth had no analgesic effect in this acute pain model.
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PMID:Effects of lamotrigine on pain-induced chemo-somatosensory evoked potentials. 1046 May 30

Antagonists of glutamate receptors of the N-methyl-d-aspartate subclass (NMDAR) or inhibitors of nitric oxide synthase (NOS) prevent nervous system plasticity. Inflammatory and neuropathic pain rely on plasticity, presenting a clinical opportunity for the use of NMDAR antagonists and NOS inhibitors in chronic pain. Agmatine (AG), an endogenous neuromodulator present in brain and spinal cord, has both NMDAR antagonist and NOS inhibitor activities. We report here that AG, exogenously administered to rodents, decreased hyperalgesia accompanying inflammation, normalized the mechanical hypersensitivity (allodynia/hyperalgesia) produced by chemical or mechanical nerve injury, and reduced autotomy-like behavior and lesion size after excitotoxic spinal cord injury. AG produced these effects in the absence of antinociceptive effects in acute pain tests. Endogenous AG also was detected in rodent lumbosacral spinal cord in concentrations similar to those previously detected in brain. The evidence suggests a unique antiplasticity and neuroprotective role for AG in processes underlying persistent pain and neuronal injury.
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PMID:Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. 1098 43

Coincident with nociception, both noxious chemical stimulation of the hind paw and chronic constriction injury (CCI) of the sciatic nerve produce an increase in protein kinase C (PKC) translocation in the spinal cord of rats. Noxious stimulus-induced PKC translocation likely depends on glutamate activity at either N-methyl-D-aspartate (NMDA) receptors or group I metabotropic glutamate receptors (mGluR1/5) in the spinal cord dorsal horn. This study compares nociceptive responses to, and the alterations in membrane-associated PKC, induced by noxious chemical stimulation of the hindpaw and CCI of the sciatic nerve, as well as their modulation by both NMDA and mGluR1/5 receptor antagonists. Three groups of rats were given a single intrathecal (i.t.) injection of either vehicle, dizocilpine maleate (MK-801, 60 nmol), an NMDA receptor antagonist, or (S)-4-carboxyphenylglycine (S)-4CPG, (150 nmol), an mGluR1/5 antagonist, 10 min prior to a 50 microl of 2.5% formalin injection into the ventral surface of one hind paw. Another three groups of rats were given twice daily injections of either vehicle, MK-801 (30 nmol) or (S)-4CPG (90 nmol) i.t. for 5 days starting 30 min before CCI or sham injury of the sciatic nerve. Nociceptive responses were assessed for a 60 min period after the formalin injection in the first three groups, and tests of mechanical and cold allodynia were performed on days 4, 8, 12 and 16 after CCI for the latter three groups. Furthermore, changes in the levels of membrane-associated PKC, as assayed by quantitative autoradiography of the specific binding of [3H]-phorbol 12,13-dibutyrate ([3H]-PDBu) in the dorsal horn of the lumbar spinal cord sections, were assessed in formalin-injected rats (at 5, 25 and 60 min) and in neuropathic rats 5 days after CCI, treated (as above) with vehicle, MK-801 or (S)-4CPG. The results indicate that i.t. treatment with MK-801 significantly reduced nociceptive scores in the formalin test and also produced a significant suppression of formalin-induced increases in [3H]-PDBu binding in laminae I-II, III-VI and X of the lumbar spinal cord. In contrast, i.t. treatment with (S)-4CPG failed to significantly affect either nociceptive behaviours in the formalin test or formalin-induced increases in [3H]-PDBu binding in laminae I-II and III-VI of the lumbar spinal cord. On the other hand, i.t. treatment with either MK-801 or (S)-4CPG produced a significant reduction in mechanical and cold hypersensitivity, as well as [3H]-PDBu binding in laminae I-II and III-VI of the lumbar spinal cord, after CCI. These results suggest that while NMDA, but not mGluR1/5, receptors are involved in translocation of PKC and nociception in a model of persistent acute pain, both types of receptors influence the translocation of PKC in dorsal horn and mechanical and cold allodynia in a model of chronic neuropathic pain.
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PMID:Differential effects of NMDA and group I mGluR antagonists on both nociception and spinal cord protein kinase C translocation in the formalin test and a model of neuropathic pain in rats. 1157 41

L-Acetylcarnitine (LAC, 100 mg/kg, s.c.), a drug commonly used for the treatment of painful neuropathies, substantially reduced mechanical allodynia in rats subjected to monolateral chronic constriction injury (CCI) of the sciatic nerve and also attenuated acute thermal pain in intact rats. In both cases, induction of analgesia required repeated injections of LAC, suggesting that the drug induces plastic changes within the nociceptive pathway. In both CCI- and sham-operated rats, a 24-day treatment with LAC increased the expression of metabotropic glutamate (mGlu) receptors 2 and 3 in the lumbar segment of the spinal cord, without changing the expression of mGlu1a or -5 receptors. A similar up-regulation of mGlu2/3 receptors was detected in the dorsal horns and dorsal root ganglia of intact rats treated with LAC for 5-7 days, a time sufficient for the induction of thermal analgesia. Immunohistochemical analysis showed that LAC treatment enhanced mGlu2/3 immunoreactivity in the inner part of lamina II and in laminae III and IV of the spinal cord. An increased mGlu2/3 receptor expression was also observed in the cerebral cortex but not in the hippocampus or cerebellum of LAC-treated animals. Reverse transcription-polymerase chain reaction combined with Northern blot analysis showed that repeated LAC injections selectively induced mGlu2 mRNA in the dorsal horns and cerebral cortex (but not in the hippocampus). mGlu3 mRNA levels did not change in any brain region of LAC-treated animals. To examine whether the selective up-regulation of mGlu2 receptors had any role in LAC-induced analgesia, we have used the novel compound LY 341495, which is a potent and systemically active mGlu2/3 receptor antagonist. LAC-induced analgesia was largely reduced 45 to 75 min after a single injection of LY 341495 (1 mg/kg, i.p.) in both CCI rats tested for mechanical allodynia and intact rats tested for thermal pain. We conclude that LAC produces analgesia against chronic pain produced not only by peripheral nerve injury but also by acute pain in intact animals and that LAC-induced analgesia is associated with and causally related to a selective up-regulation of mGlu2 receptors. This offers the first example of a selective induction of mGlu2 receptors and discloses a novel mechanism for drug-induced analgesia.
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PMID:L-Acetylcarnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glutamate receptors. 1196 Nov 16

The undecapeptide substance P is expressed by primary afferent neurons where it is considered to be a cotransmitter of other peptides and glutamate. Since it is predominantly found in sensory neurons with unmyelinated fibres (C-fibres), substance P has long been thought to be a "pain transmitter". Following stimulation of nociceptive afferents, substance P is released in the spinal cord and substance P-mediated transmission is primarily brought about by tachykinin NK1 receptors. To inhibit this process, a considerable number of non-peptide, highly potent, highly selective and brain penetrant NK1 receptor antagonists have been developed during the past decade. Experimental studies have proved that NK1 receptor antagonists are indeed able to blunt pain in sensitized states and thus to reverse hyperalgesia, whereas acute pain is left fairly unchanged. The hyperalgesic role of substance P has been corroborated by the sensory deficits seen in substance P and NK1 receptor knockout mice. However, the concept that NK1 receptor antagonists would represent a novel class of analgesic drugs, as suggested by the preclinical studies, has not been borne out by the clinical trials that have been reported thus far. This article offers an overview of those hyperalgesic conditions in which NK1 receptor antagonists may be of therapeutic value and discusses possible reasons for the discrepancies between preclinical and clinical trials with NK1 receptor antagonists.
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PMID:[Why are substance P(NK1)-receptor antagonists ineffective in pain treatment?]. 1206 23

Experimental evidence suggests that release of neurotransmitters in response to acute noxious stimulation and inflammation can differ in superficial and deeper dorsal horn (DH) laminae. Using two different microdialysis probes, we studied changes in levels of glutamate, aspartate, arginine and GABA in dialysates collected from the surface of the spinal cord and within the DH induced by pinching the paw or paw inflammation. In penthotal anaesthetized rats, a flexible microdialysis probe was placed on the dorsal surface of the L4-L5 or L6-S2 spinal segments. In other rats, a rigid microdialysis probe was implanted within the DH of the same segments. Samples were collected every minute before, during and after pinching the hind paw (acute pain), and every half an hour after injecting either carrageenan or saline into the same paw (inflammation-induced pain). Amino acids were measured by capillary zone electrophoresis with laser-induced fluorescence detection (CZE-LIFD). Pinching the paw induced a significant but short lasting increase in extracellular glutamate and aspartate in dialysates from the surface of the DH. Carrageenan, but not saline, injected into the paw significantly increased concentrations of glutamate, aspartate and arginine both on the surface and within the DH of L4-L5 and also within the DH of the L6-S2 segments. The GABA level was significantly increased following carrageenan only within the DH. The maximum increase on the surface was detected 60-120 min after the onset of inflammation whereas the response within the DH reached a maximum between 150 and 180 min after carrageenan. These results indicate that unlike acute mechanical noxious stimulation which enhances amino acid neurotransmitters in surface dialysate, inflammation induced neurotransmitter release in all layers of the DH suggesting sensitization of the DH.
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PMID:Differential release of neurotransmitters from superficial and deep layers of the dorsal horn in response to acute noxious stimulation and inflammation of the rat paw. 1510 75

Pain is a sensation we have all experienced. For most of us, the pain has been temporary. However, for patients with pathological pain, the pain experience is unending, with little hope for therapeutic relief. Pathological pain is characterized by an amplified response to normally innocuous stimuli, and an amplified response to acute pain. Pathological pain has long been described as the result of dysfunctional neuronal activity. While neuronal functioning is indeed altered, there is significant evidence showing that exaggerated pain is regulated by the activation of astrocytes and microglia. In exaggerated pain, astrocytes, and microglia are activated by neuronal signals including substance P, glutamate, and fractalkine. Activation of glia by these substances leads to the release of mediators that then act on other glia and neurons. These include a family of proteins called "proinflammatory cytokines" released from microglia and astrocytes. These cytokines have been shown to be critical mediators of exaggerated pain. Some patients with pathological pain also report "extra-territorial" and/or "mirror" image pain. That is, exaggerated pain is experienced not only in the area of trauma. In extra-territorial pain, pain is also perceived as arising from neighboring healthy tissues outside of the site of trauma. In the rare cases of mirror-image pain, such pain is perceived as arising from the healthy, corresponding body part on the opposite side of the body. New data suggest that activation of astrocyte communication via gap junctions may mediate such spread of pain. While traditional therapies for pathological pain have focused on neuronal targets, the following review describes glia as newly recognized mediators of exaggerated pain, and as new therapeutic targets. Moreover, the glial-neuronal interactions discussed here are likely not exclusive to pain, but rather are likely to play significant roles in other behavioral phenomena.
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PMID:Glial activation and pathological pain. 1514 53


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