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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In awake, freely moving rats, the intracerebral administration of the excitatory amino acid L-glutamate (30 nmol/0.5 microliters) into discrete regions of the brainstem resulted in a transient and spontaneous pain-like syndrome characterized by an initial vocalization and vigorous escape behavior. Systematic microinjection mapping studies were carried out at sites distributed caudally from the lower medulla and rostrally into diencephalon. These studies revealed that the spontaneous pain-like behavior was observed to occur after glutamate injection in 13% of 331 microinjected sites, and these sensitive sites were largely limited to the mesencephalic periaqueductal gray matter. The behavioral syndrome was dose-dependent and antagonized in a dose-dependent fashion by the glutamate receptor antagonists MK 801 and DL-2-amino-5 phosphonovalerate but not by gamma-D-glutamyl-amino-methylsulfonic acid. The pain-like behavior was also produced by the other excitatory amino acid receptor agonists N-methyl-D-aspartate, quisqualate and to a certain extent by kainate in a dose-dependent manner with the order of potency being N-methyl-D-aspartate = kainate greater than quisqualate greater than D-glutamate. The effects of N-methyl-D-aspartate and quisqualate were antagonized by MK 801 and DL-2-amino-5 phosphonovalerate but not by gamma-D-glutamyl-amino-methylsulfonic acid. It is suggested that the pain-like behavioral syndrome is the result of focal occupation of N-methyl-D-aspartate receptors on neuronal populations in the terminal regions of rostrally projecting spinomesencephalic systems.
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PMID:Brainstem excitatory amino acid receptors in nociception: microinjection mapping and pharmacological characterization of glutamate-sensitive sites in the brainstem associated with algogenic behavior. 134 50

Intrathecal administration of glycine (strychnine) or GABA (bicuculline) but not opioid (naloxone), adrenergic (phentolamine) or serotonin (methysergide) receptor antagonists resulted in a dose-dependent organized agitation response to light tactile stimulation. This effect was maximally evoked by oscillating but not continuous stimulation applied to a dermatome corresponding to the levels of spinal cord acted upon by the intrathecal antagonist. Similar results were observed in chloralose-urethane anesthetized rats in which tactile stimulation evoked hypertensive responses following local tactile stimuli. The effects were only mildly depressed by even high doses of spinal morphine or DADL and not at all by ST-91 or baclofen. In contrast, intrathecal injections of glutamate receptor antagonists resulted in a dose-dependent depression of the strychnine evoked hyperesthesia with the ordering of activity being MK-801, AP-5, kynurenic acid, SKF10047 and ketamine. At doses below those which produced motor dysfunction, however, these agents had no effects on the hot-plate response latency. These data emphasize that low threshold afferent input is likely subject to an ongoing modulation, the loss of which results in a miscoding of the afferent stimulus yielding a pain relevant message. The lack of effect of agents having a powerful effect on somatic pain stimuli and the converse effects of glutamate receptor antagonists on the strychnine hyperesthesia at doses which do not affect the somatic pain response indicate discriminable processing systems, the characteristics of which resemble the clinical phenomenon observed in patients suffering from sensory dysesthesia following central and peripheral horn injury.
Pain 1989 Apr
PMID:Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. 254 67

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor are of considerable interest for various neurotherapeutic purposes, including preventing neuronal degeneration in stroke and CNS trauma, suppressing neuropathic pain and preventing the development of tolerance to opiate analgesics. Unfortunately, NMDA antagonists can cause potentially serious side effects, including acute neurodegenerative changes in corticolimbic regions of the adult rat brain and psychotic reactions in adult humans. We have been investigating the mechanisms underlying the neuropathological changes in rat brain and exploring methods of suppressing or preventing such changes. Here we report that alpha 2 adrenergic agonists can prevent NMDA antagonist neurotoxicity. Therefore, administering alpha 2 adrenergic agonists together with NMDA antagonists may be a valuable strategy for preventing adverse side effects of NMDA antagonists and making these agents safer for various neurotherapeutic purposes.
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PMID:alpha 2 adrenergic agonists prevent MK-801 neurotoxicity. 757 11

We recently reported that intrathecal (i.t.) administration of prostaglandin (PG) E2 or PGF2 alpha in conscious mice induced allodynia through a pathway that includes the glutamate receptor system. Allodynia induced by PGE2 and PGF2 alpha was blocked by antagonists for NMDA and metabotropic glutamate receptor subtypes, respectively. In the present study, we examined the possibility for the involvement of nitric oxide (NO) in the PG-evoked allodynia. Allodynia was assessed once every 5 min by light stroking of the flank of mice with a paintbrush. Intrathecal administration of L-arginine, a substrate of nitric oxide synthase (NOS), in conscious mice resulted in allodynia. Dose dependency of L-arginine for allodynia showed a bell-shaped pattern (1-10 micrograms/mouse). The maximal allodynic effect was observed with 5.0 micrograms at 10-15 min after i.t. injection, similar in time course and magnitude to that induced by L-glutamate. L-Arginine-induced allodynia was dose-dependently reduced by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue with IC50 values of 7.68 and 8.70 pg/mouse, respectively. PGE2-induced allodynia was also dose-dependently inhibited by L-NAME and methylene blue with IC50 values of 94.7 and 74.9 pg/mouse. PGF2 alpha-induced allodynia was inhibited by methylene blue with an IC50 value of 40.6 pg/mouse, but not by L-NAME at doses up to 1.0 ng.(ABSTRACT TRUNCATED AT 250 WORDS)
Pain 1995 May
PMID:Nitric oxide mediates allodynia induced by intrathecal administration of prostaglandin E2 or prostaglandin F2 alpha in conscious mice. 765 39

In order to investigate the involvement of glutamate receptor systems in allodynia induced by prostaglandin (PG) E2 or F2 alpha, we co-administered antagonists for N-methyl-D-aspartate (NMDA), non-NMDA, or metabotropic glutamate receptors intrathecally with PGE2 or PGF2 alpha and examined their effects on the allodynia evoked in conscious mice by non-noxious brushing of the flanks. MK-801, a non-competitive NMDA receptor channel blocker, and D-AP-5, a selective NMDA receptor antagonist, dose-dependently blocked PGE2-induced allodynia with an IC50 of 1.60 and 0.52 microgram/mouse, respectively. A glycine binding-site antagonist for the NMDA receptor, 7-Cl-KYNA, did not influence it. None of these NMDA receptor antagonists inhibited PGF2 alpha-evoked allodynia. Non-NMDA receptor antagonists GAMS and CNQX inhibited both PGE2- and PGF2 alpha-induced allodynia. On the other hand, L-AP-3 and L-AP-4, putative metabotropic glutamate receptor antagonists, dose-dependently antagonized the allodynia induced by PGF2 alpha with an IC50 of 0.92 and 3.26 ng/mouse, respectively, but not that induced by PGE2. Intrathecal administration of L-glutamate produced allodynia over a wide range of low doses from 0.1 pg to 0.1 microgram/mouse, and the maximal effect was observed at 1 ng. Similar to allodynia induced by prostaglandins, the response lasted over a 50-min experimental period. These results demonstrate that both PGE2- and PGF2 alpha-evoked allodynia are mediated through a pathway that includes the glutamate receptor system but that subtypes of glutamate receptors involved and sites of action in the spinal cord may be different between them.
Pain 1994 May
PMID:Involvement of glutamate receptors in allodynia induced by prostaglandins E2 and F2 alpha injected into conscious mice. 791 53

Dorsal horn sensitization following somatic noxious stimuli is partly mediated by the N-methyl-D-aspartate (NMDA) sub-type of glutamate receptor. This phenomenon has been comparatively sparsely investigated in the area of visceral pain. We have therefore investigated the role of spinal NMDA receptors in central sensitization in an animal model of persistent visceral pain. In anaesthetized rats the lumbosacral spinal cord was exposed by laminectomy and the pre-emptive effect of intrathecal AP-5 upon the hyper-reflexia associated with chemical inflammation of the bladder was investigated. The effect of intrathecal AP-5 (an NMDA receptor antagonist) upon the normal cystometrogram (CMG) was also measured. AP-5 (125-1000 micrograms) prevented the hyper-flexia associated with bladder inflammation in a dose-dependant fashion. In general, within the dose range 62.5-1000 micrograms, AP-5 had no significant effect upon the normal micturition reflex. However, at the top of this dose range a minor non-significant depression of this reflex was noted. NMDA receptors do not appear to mediate the micturition reflex at a spinal cord level. However, they are involved in the induction of hyper-reflexia following urinary bladder inflammation, this hyper-reflexia can be prevented by pre-emptive intrathecal administration of AP-5.
Pain 1994 Jun
PMID:Pre-emptive intrathecal administration of an NMDA receptor antagonist (AP-5) prevents hyper-reflexia in a model of persistent visceral pain. 793 11

5-Chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) has analgesic properties in animal models of tonic pain. To investigate the mechanisms underlying this effect we used electrical recording techniques to characterize the in vitro pharmacology of ACEA-1011 at mammalian glutamate receptors. Two preparations were used: Xenopus oocytes expressing rat brain receptors and cultured rat cortical neurons. Results showed that ACEA-1011 is a competitive antagonist at NMDA receptor glycine sites. Apparent antagonist affinities (Kb values) were 0.4 to 0.8 microM in oocytes and approximately 0.6 microM in neurons. IC50 values for ACEA-1011 against four binary subunit combinations of cloned rat NMDA receptors (NR1A/NR2A, 2B, 2C or 2D) ranged from 0.4 to 8 microM (1 microM glycine). The 20-fold variation in sensitivity was due to a combination of subunit-dependent differences in glycine and antagonist affinities; EC50 values for glycine ranged between 0.08 to 0.8 microM and Kb values for ACEA-1011 between 0.2 to 0.8 microM. In addition, ACEA-1011 inhibited AMPA-preferring non-NMDA receptors by competitive antagonism at glutamate binding sites. Kb values were 4 to 9 microM in oocytes and 9 to 10 microM in neurons. The ED50 for ACEA-1011 in a mouse maximum electroshock-induced seizure model was approximately 12 mg/kg i.v.. Our results indicate that ACEA-1011 is a systemically active broad selectivity ionotropic glutamate receptor antagonist.
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PMID:Pharmacology of 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione: a novel systemically active ionotropic glutamate receptor antagonist. 853 Oct 83

Immunohistochemical staining for the glutamate receptor subtypes N-methyl-D-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) results in a significant number of labeled unmyelinated axons in the glabrous skin of the rat hindpaw. Injection of glutamate into the rat hindpaw results in behavioral changes interpreted as mechanical allodynia and mechanical hyperalgesia. The anatomical findings provide a reasonable explanation for the action of the exogenous peripheral glutamate, namely that activation of these receptors leads to increased primary afferent activity in unmyelinated axons and thus to pain behaviors. AMPA receptors are frequently associated with small clear vesicles in the axoplasm of the unmyelinated axons, many of which have been previously shown to contain high concentrations of glutamate. This finding indicates that these might be autoreceptors and so glutamate itself might regulate certain types of peripheral impulse traffic. The presence of peripheral glutamate receptors associated with unmyelinated axons suggests the possibility that glutamate antagonists applied peripherally might prevent or attenuate some pain-related behaviors.
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PMID:Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. 854 47

The present study investigated the role of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor subtypes in peripheral pain transmission. Activation of NMDA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate acid (KA) receptors in glabrous skin of the rat hindpaw resulted in mechanical allodynia and mechanical hyperalgesia. These agonist-induced pain behaviors were attenuated following peripheral injection of appropriate antagonists (MK-801 and CNQX). Thus, activation of NMDA, AMPA or KA receptors at the level of the peripheral nerve terminal can produce nociceptive behavior. These data suggest that topical application of glutamate receptor antagonists may be useful in treating pain disorders. Since all three receptor subtypes are involved in peripheral pain transmission, however, it will be necessary to antagonize multiple glutamate receptor subtypes to achieve effective pain relief.
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PMID:Peripheral administration of NMDA, AMPA or KA results in pain behaviors in rats. 872 68

We recently reported that intrathecal (i.t.) administration of prostaglandin E2 (PGE2) to conscious mice induced allodynia, a state of discomfort and pain evoked by innocuous tactile stimuli. In the present study, we examined the effect of the PGE receptor EP1 subtype antagonist ONO-NT-012, the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, and the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on the allodynia. The PGE2-induced allodynia was blocked by simultaneous i.t. injection of ONO-NT-012, MK-801, or L-NAME. However, 5 min after i.t. injection of PGE2, the allodynia was significantly blocked by i.t. L-NAME, but not by i.t. ONO-NT-012 or MK-801. These results demonstrate that the PGE2-induced allodynia, once developed, does not require the continued agonist occupancy of EP1 and NMDA glutamate receptor sites.
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PMID:L-NAME, an inhibitor of nitric oxide synthase, blocks the established allodynia induced by intrathecal administration of prostaglandin E2. 878 49


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