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

The hypothesis tested was that inhibition of the L-arginine-nitric oxide (NO) pathway may represent a potential central mechanism of action for acetaminophen (paracetamol). Spinal administration of N-methyl-D-aspartate (NMDA, 0.5 nmol), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, 0.1 nmol) or substance P (SP, 0.5 nmol) to the rat provoked a specific behaviour characterized by biting, scratching and licking (BSL). This behaviour was antagonized by pretreatment with acetaminophen for NMDA and SP but not for AMPA. Further, the antinociceptive effect of acetaminophen was readily reversed by administration of the natural substrate for nitric oxide synthase (NOS), L-arginine, but not by D-arginine. This suggests that the analgesic effect of acetaminophen is related to inhibition of NO generation. Potential mechanisms for this may involve NMDA and SP. Our data suggest that a significant portion of the analgesic effect of acetaminophen, when used clinically, may be related to an interaction with the central nervous system L-arginine-NO pathway.
Pain 1994 Jun
PMID:Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. 752 8

Results of neurophysiologic and behavioral studies suggest that excitatory amino acid (EAA) antagonists may provide a new class of analgesic agents, which might be selective for neuropathic pain states that are resistant to opiate treatment. Most of these paradigms involve animal models of peripheral injury. The present study evaluated the antinociceptive effect of spinally [intrathecally (IT)] administered EAA antagonists after central injury, produced by spinal transection. Intrathecal injection of the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione produced dose-dependent antinociception on the thermal tail withdrawal [tail-flick (TF)] reflex test in Intact rats, which was significantly potentiated after spinal transection. In contrast, IT injection of the NMDA antagonist, 2-amino-5-phosphonopentanoic acid (AP5) did not affect the TF in intact rats, but significantly blocked this response in spinal rats. However, some of the spinal rats did not recover the reflex, suggesting a possible toxic action of AP5.
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PMID:Selective antinociceptive effect of excitatory amino acid antagonists in intact and acute spinal rats. 767 69

In anaesthetized rats antinociceptive effects of the clinically available drug memantine, an NMDA (N-methyl-D-aspartate) antagonist in vitro, were evaluated using extracellular recordings from spinal neurones with knee joint input. Memantine (1-12 mg kg-1) was applied intravenously before (control animals) or after induction of an acute knee joint inflammation which rendered spinal neurones hyperexcitable. Memantine (2 mg kg-1, i.v.) selectively reduced the responses to ionophoretic application of NMDA close to the neurone but not those to AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid). In control animals memantine reduced the neurones' responses to noxious but not to innocuous pressure on to the knee. In rats with acute arthritis memantine reduced the responses to noxious and innocuous pressure. Thus memantine may be useful for the treatment of pain states.
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PMID:The clinically available NMDA receptor antagonist memantine is antinociceptive on rat spinal neurones. 769 15

Synaptic transmission between dorsal root afferents and neurons in the superficial laminae of the spinal dorsal horn (laminae I-III) was examined by intracellular recording in a transverse slice preparation of rat spinal cord. Brief high-frequency electrical stimulation (300 pulses at 100 Hz) of primary afferent fibers produced a long-term potentiation (LTP) or a long-term depression (LTD) of fast (monosynaptic and polysynaptic) EPSPs in a high proportion of dorsal horn neurons. Both the AMPA and the NMDA receptor-mediated components of synaptic transmission at the primary afferent synapses with neurons in the dorsal horn can exhibit LTP and LTD of the synaptic responses. In normal and neonatally capsaicin-treated rats, the induction of LTP requires the activation of NMDA receptor-gated conductances. The induction of LTP or LTD, however, was not abolished in the presence of bicuculline, a GABAA receptor antagonist. The results demonstrate that distinct and long-lasting modulation in synaptic efficiency can be induced at primary afferent synapses with neurons in the superficial laminae of spinal dorsal horn by high-frequency stimulation of dorsal root afferents and that these changes may be physiologically relevant for transmission and integration of sensory information, including pain.
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PMID:Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. 825 70

The rat isolated spinal cord-tail preparation has been employed to examine the effects of several antinociceptive drugs and excitatory amino acid (EAA) receptor antagonists on nociceptive reflexes (recorded in ventral roots) stimulated by peripheral application of capsaicin (CAP). Non-nociceptive monosynaptic and polysynaptic dorsal root-evoked ventral root potentials (DR-VRPs) were also examined. Morphine (0.01-3 microM) and clonidine (0.03-1 microM) inhibited CAP-stimulated activity, but not the non-nociceptive dorsal root-evoked monosynaptic reflex (MSR) or polysynaptic (PSR) activity. These effects were antagonized by naloxone and efaroxan, respectively. The AMPA/KA receptor antagonists CNQX (0.1-100 microM) and DNQX (0.1-30 microM) blocked nociceptive activity and were 4-fold selective for CAP-evoked potentials compared to the monosynaptic reflex. Kynurenate (1-300 microM), DL-AP-4 (3-300 microM), L-AP-4 (3-300 microM), and the GABAB receptor agonist baclofen (0.1-10 microM), inhibited all evoked potentials with relatively little selectivity between nociceptive and non-nociceptive responses. NMDA receptor antagonism by AP-5 (100 microM) reduced nociceptive and non-nociceptive potentials by a maximum of 30-33%. These data indicate that AMPA/KA receptor-mediated synapses are involved in acute spinal nociceptive transmission and suggest that AMPA/KA receptor subtypes could provide novel analgesic targets.
Pain 1993 Mar
PMID:Effects of excitatory amino acid receptor antagonists on a capsaicin-evoked nociceptive reflex: a comparison with morphine, clonidine and baclofen. 846 52

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

Supraspinal opioid analgesia is mediated in part by connections between the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). Morphine analgesia elicited from the PAG is respectively decreased by selective serotonergic and opioid receptor antagonists administered into the RVM, and increased by RVM neurotensin antagonists. Since glutamate and excitatory amino acid (EAA) receptors are also active in the RVM, the present study evaluated whether either competitive (AP7) or non-competitive (MK-801) N-methyl-D-aspartate (NMDA) antagonists or a kainate/AMPA (CNQX) antagonist microinjected into the RVM altered morphine (2.5 micrograms) analgesia elicited from the PAG as measured by the tail-flick and jump tests. Mesencephalic morphine analgesia was markedly reduced on both tests after RVM pretreatment with either AP7 (0.01-1 microgram, 0.08-7.8 nmol) or MK-801 (0.03-3 micrograms, 0.04-4.4 nmol). In contrast, small but significant reductions in mesencephalic morphine analgesia occurred on the jump test following CNQX (0.5 microgram, 2.2 nmol) in the RVM. NMDA antagonists did not markedly alter either basal nociceptive thresholds following RVM administration, or mesencephalic morphine analgesia following administration into medullary placements lateral or dorsal to the RVM. These data implicate EAA and particularly NMDA receptors in the RVM in modulating the transmission of opioid pain-inhibitory signals from the PAG.
Pain 1996 Mar
PMID:Excitatory amino acid antagonists in the rostral ventromedial medulla inhibit mesencephalic morphine analgesia in rats. 878 20

In mice injected with formalin into the hindpaw, the 5-HT1A receptor agonists, 8-OH-DPAT and flesinoxan, equipotently inhibited the early phase (EP) and late phase (LP) of licking. At higher doses, they provoked ataxia and inhibited the writhing elicited by intra-abdominal acetic acid. The antagonists, (-)-alprenolol, (-)-tertatolol, WAY-100,135 and S 15931 were more potent against the LP than the EP. They also inhibited writhing, and only at very high doses did they elicit ataxia. In rats, 8-OH-DPAT and flesinoxan increased the current required to elicit vocalisation upon electrical stimulation of the tail. The action of 8-OH-DPAT was blocked by WAY-100,135, which, like other antagonists, was inactive alone. Interestingly, a low dose of 8-OH-DPAT partially inhibited the antinociceptive action of the mu-opioid agonist, morphine, the action of which was dose-dependently facilitated by (-)-alprenolol and S 15931. Administered s.c., 8-OH-DPAT elicited spontaneous tail-flicks (STFs) in rats: these were abolished by WAY-100,135, (-)-tertatolol, (-)-alprenolol and S 15931. STFs were also eliminated by s.c. or i.t. administration of the alpha 2-adrenergic receptor agonist, clonidine, the GABAA agonist, muscimol or the GABAB agonist, baclofen. The mu-opioid, morphine, blocked STFs only at high doses and the kappa-opioid agonists, U 50,488 and U 69,593, even at supra-ataxic doses, were inactive. Antagonists at neurokinin (NK)1 (RP 67580), NK2 (SR 48,968) and bradykinin (BK)2 (Hoe 140) receptors, as well as aspirin, did not block STFs, though indomethacin was effective. Antagonists at the glycine B site coupled to the NMDA receptor, L 687,414, L 701,324 and (+)-HA966, blocked STFs. Furthermore, (+)-HA 966 and the competitive NMDA receptor antagonist, CPP, were active upon i.t. administration. STFs were also blocked by s.c. or i.t. administration of the AMPA antagonists, YM 900 and NBQX. In conclusion, the influence of 5-HT1A ligands upon nociception is dependent upon the algesiometric paradigm. Intriguingly, modulation of 5-HT1A receptor-mediated STFs reveals parallels to neuropathic pain.
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PMID:Pro- and antinociceptive actions of serotonin (5-HT)1A agonists and antagonists in rodents: relationship to algesiometric paradigm. 878 80

Recent studies indicate that glutamate binding to N-methyl-D-aspartate receptors in the spinal cord is involved in triggering the development of chronic pain However, the processes which directly underlie the increased pain remain unclear. Here we report that, following peripheral nerve injury (ligation of the sciatic nerve) in the rat, there is an increase in immunoreactive labelling of non-N-methyl-D-asparatate, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate), glutamate receptors in the superficial laminae of the lumbar spinal cord ipsilateral to the ligation. The increase in AMPA receptor expression peaks 14 days after nerve ligation and decreases 35 days post-ligation, corresponding to the time-course of heightened sensitivity to mechanical and thermal noxious stimuli (hyperalgesia) induced by the ligation. Given evidence that AMPA receptors in the superficial laminae mediate fast nociceptive transmission in the spinal cord, our findings suggest that an upregulation of spinal AMPA receptors contributes to hyperalgesia following peripheral nerve injury.
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PMID:Upregulation of spinal glutamate receptors in chronic pain. 884 72

The study aimed at identifying some of the receptors for neurotransmitters/neuromodulators that are involved in the myositis-induced neuroplastic changes in spinal neurones. In anaesthetised rats, an experimental myositis was induced in the gastrocnemius-soleus muscle and the activity of single dorsal horn neurones recorded in the segment L3, just rostral to the main input region from that muscle. During the development of the myositis, the segment L3 was continuously superfused with antagonists to neurokinin receptors (GR 82.334, Spantide II), NMDA receptors (MK-801, AP 5) or AMPA/kainate receptors (CNQX). Each of the antagonists reduced the myositis-induced increase in excitability, but acted on different aspects of the hyperexcitability. GR 82.334 was most effective in preventing the expansion of the neurone population that responded to A-fibre input from the inflamed muscle, which was the main myositis effect in the present study. None of the antagonists influenced the background activity of the neurones. The results show that in the myositis-induced hyperexcitability of dorsal horn neurones all of the above receptors are involved. Excitability by peripheral input and background activity of the neurones are probably controlled by different mechanisms.
Pain 1997 Feb
PMID:Myositis-induced functional reorganisation of the rat dorsal horn: effects of spinal superfusion with antagonists to neurokinin and glutamate receptors. 908 95


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