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)

Analgesia has been reported to be facilitated by supraspinal nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). In the rostromedial medulla, an important pain-suppressing region, iontophoretically delivered 8-bromo-cGMP excited most single recorded cells (9/10), and methylene blue (a guanylyl cyclase inhibitor) inhibited all cells (7/7). Nitrite and ferrous ions together, shown voltammetrically ex vivo to yield nitric oxide (NO), excited some cells (14/28) and inhibited others (7/28). Methylene blue blocked excitation (3/3) but not inhibition (4/4) by the putative NO. Spontaneous or glutamate-evoked firing was gradually inhibited (23/32) or unaffected by N omega-nitro-L-arginine (a NO synthase inhibitor), but was mostly inhibited by L-arginine (the NO precursor) (23/26), although a rapid onset militated against elevated NO production. These substances, excepting L-arginine, produced changes consistent with an excitatory cGMP-NO cascade contributing to analgesia.
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PMID:Excitation of cells in the rostral medial medulla of the rat by the nitric oxide-cyclic guanosine monophosphate messenger system. 858 98

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.
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PMID:Excitatory amino acid antagonists in the rostral ventromedial medulla inhibit mesencephalic morphine analgesia in rats. 878 20

Although ketamine has been in clinical use for 3 decades, the neuropharmacological basis of its analgesic, anaesthetic, sympathomimetic, and psychotomimetic effects is still a subject of controversial discussion and intensive investigational efforts. In recent years, however, new experimental approaches to its effects on the cellular and molecular level and the availability of pure ketamine enantiomers contributed substantially to the understanding of its complex neuropharmacology. This article reviews the current knowledge of ketamine effects on ligand-operated and voltage-operated transmembrane ion channels, G-protein-coupled receptors, transmitter uptake, and the NO-cGMP system in neurons. With regard to its potential clinical relevance and supposed relative role among the complex mechanisms involved in pain perception, analgesia, anaesthesia, and psychotomimesis, the contributions of recent experimental and clinical findings to the identification of major target sites of ketamine are summarised. In contrast to the uncertainty surrounding the potential role of opioid receptors, there is now considerable evidence that NMDA antagonism is a central mechanism that contributes to the amnesic, analgesic, anaesthetic, and psychotomimetic as well as the neuroprotective actions of ketamine. Moreover, the involvement of non-NMDA glutamate receptors, muscarinic and nicotinic cholinergic transmission, interactions with 5-HT receptors, and L-Type Ca2+ channels may account for some of its anaesthetic and neuroprotective properties.
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PMID:[Mechanisms of action of ketamine]. 916 83

Vaginocervical stimulation (VS) releases multiple neurotransmitters into superfusates of the spinal cord; these can stimulate both nociceptive (e.g., glutamate, and glycine acting at the NMDA site), and antinociceptive (e.g., GABA, norepinephrine, 5-HT, and glycine acting at the strychnine-sensitive receptor) systems. Although the balance between these two opposing systems can determine the nature, magnitude, and duration of the response to VS, the characteristic prevailing response to VS is analgesia. We hypothesized that by counteracting the nociceptive component of this system, the magnitude and duration of the response to VS would be augmented. In the present study, the NMDA receptor antagonist AP5 [10 microg injected intrathecally (i.t.)] significantly increased the magnitude and duration of the analgesia (measured as tail flick latency to radiant heat) produced by VS (200 g force). At several time points the analgesic effect of AP5 combined with VS was greater than the sum of the effects of AP5 and VS separately, suggesting that they act synergistically. We propose that AP5 potentiates the analgesic effect of VS by two mechanisms: (a) antagonizing the putative pain-producing action of glutamate and glycine acting jointly at the NMDA receptor, and consequently, (b) permitting the unimpeded expression of the analgesic action of inhibitory neurotransmitters released by VS (e.g., glycine at the strychnine-sensitive receptor, and GABA).
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PMID:Analgesic synergism between AP5 (an NMDA receptor antagonist) and vaginocervical stimulation in the rat. 971 6

Electrophysiological and behavioral studies point to a role of group I metabotropic glutamate receptors (mGluR1 and mGluR5) in mediating spinal nociceptive responses in rats. However, antagonists with a high degree of specificity for each of these sites are not yet available. We, therefore, examined the effects of antisense deletion of spinal mGluR1 expression in assays of behavioral analgesia and of electrophysiological responses of dorsal horn neurons. Rats treated with an mGluR1 antisense oligonucleotide reagent, delivered continuously to the intrathecal space of the lumbar spinal cord, developed marked analgesia as measured by an increase in the latency to tail-flick (55 degreesC) over a period of 4-7 d. This correlated with a selective reduction in mGluR1, but not mGluR5, immunoreactivity in the superficial dorsal horn compared with untreated control rats, in parallel with a significant reduction in the proportion of neurons activated by the mGluR group I agonist 3, 5-dihydroxyphenylglycine (DHPG), whereas the proportion of cells excited by the mGluR5 agonist, trans-azetidine-2,4-dicarboxylic acid (t-ADA) remained unaffected. In contrast, rats treated with mGluR1 sense or mismatch probes showed none of these changes compared with untreated, control rats. Furthermore, multireceptive dorsal horn neurons in mGluR1 antisense-treated rats were strongly excited by innocuous stimuli to their peripheral receptive fields, but showed severe reductions in their sustained excitatory responses to the selective C-fiber activator mustard oil and in responses to DHPG.
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PMID:Antisense ablation of type I metabotropic glutamate receptor mGluR1 inhibits spinal nociceptive transmission. 982 71

The contribution of metabotropic glutamate receptors (mGluRs) to the modulation of nociception by the periaqueductal gray (PAG) matter was investigated in mice. Intra-PAG microinjection of (IS,3R)-ACPD, an agonist of groups I and II mGluRs, as well as (S)-3,5-DHPG, a selective agonist of group I mGluRs, increased the latency of the nociceptive reaction (NR) in the hot plate test. (RS)-AIDA, an antagonist of group I mGluRs, antagonized the effect of (S)-3,5-DHPG, but changed the effect induced by (1S,3R)-ACPD in that a decrease in the latency for the NR could now be observed. L-CCG-I and L-SOP, which are agonists of groups II and III mGluRs respectively, decreased the latency of the NR. (2S)-alpha-EGlu and (RS)-alpha-MSOP, which are antagonists of groups II and III mGluRs, respectively, antagonized the effect of L-CCG-I and L-SOP. (RS)-AIDA and (RS)-alpha-MSOP alone decreased and increased, respectively, the latency of the NR with the highest doses used. (2S)-alpha-EGlu alone did not change significantly the latency of the NR. Intra-PAG microinjection of LH, an agonist of ionotropic glutamate receptors, induced a dose-dependent analgesia which was blocked by pretreatment with DL-AP5, a selective antagonist of NMDA receptors. No mGluRs antagonists were able to prevent LH-induced analgesia. These results emphasize the possible involvement of mGluRs in the modulation of nociception. It seems that activation of group I mGluRs potentiates, while groups II and III mGluRs decrease, the activity of the PAG for the modulation of nociception.
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PMID:Characterisation of mGluRs which modulate nociception in the PAG of the mouse. 988 70

Understanding the plasticity of pain and analgesia exhibited in different pain states may improve therapies for the two major types of pain, neuropathic and inflammatory pain, in which nerve and tissue damage leads to alterations at both peripheral and central levels. At the level of the peripheral nerve, drugs that act on particular sodium channels may target only pain-related activity. Agents that act on some of the peripheral mediators of pain may control peripheral nerve activity. A new generation of non-steroidal anti-inflammatory drugs, cyclo-oxygenase 2 inhibitors, that lack gastric actions are becoming available. In the spinal cord, the release of peptides and glutamate causes activation of multiple receptors, particularly, the N-methyl-D-aspartate receptor for glutamate, which, in concert with other spinal systems, generates spinal hypersensitivity. Blocking the generation of excitability is one approach, but increasing inhibitions may also provide analgesia. Opioid actions are via presynaptic and post-synaptic inhibitory effects on central and peripheral C fibre terminals, spinal neurones, and supraspinal mechanisms. Our knowledge of brain mechanisms of pain is still, however, limited. Other new targets have been revealed by molecular biology and animal models of clinical pain, but the possibility of a "magic bullet" is doubtful. Thus, another approach could be single molecules with dual drug actions, that encompass targets where additive or synergistic effects of different mechanisms may enable pain relief without major adverse effects.
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PMID:The neurobiology of pain. 1033 74

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

Pain is detected by two different types of peripheral nociceptor neurons, C-fiber nociceptors with slowly conducting unmyelinated axons, and A-delta nociceptors with thinly myelinated axons. During inflammation, nociceptors become sensitized, discharge spontaneously, and produce ongoing pain. Prolonged firing of C-fiber nociceptors causes release of glutamate which acts on N-methyl-D-aspartate (NMDA) receptors in the spinal cord. Activation of NMDA receptors causes the spinal cord neuron to become more responsive to all of its inputs, resulting in central sensitization. NMDA-receptor antagonists, such as dextromethorphan, can suppress central sensitization in experimental animals. NMDA-receptor activation not only increases the cell's response to pain stimuli, it also decrease neuronal sensitivity to opioid receptor agonists. In addition to preventing central sensitization, co-administration of NMDA-receptor antagonists with an opioid may prevent tolerance to opioid analgesia.
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PMID:Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. 1068 31

It is well documented that the descending endogenous analgesia system, including the periaqueductal gray (PAG) and the rostral ventral medulla (RVM), play an important role in modulation of nociceptive transmission and morphine- and cannabinoid-produced analgesia. Neurons in the PAG receive inputs from different nuclei of higher structures, including the anterior cingulate cortex (ACC). However, it is unclear if stimulation of neurons in the ACC modulates spinal nociceptive transmission. The present study has examined the effects of electrical stimulation and chemical activation of metabotropic glutamate receptors (mGluRs) in the ACC on a spinal nociceptive tail-flick (TF) reflex induced by noxious heating. Activation of the ACC at high intensities (up to 500 microA) of electrical stimulation did not produce any antinociceptive effect. Instead, at most sites within the ACC (n = 36 of 41 sites), electrical stimulation produced significant facilitation of the TF reflex (i.e. decreases in TF latency). Chemical activation of mGluRs within the ACC also produced a facilitatory effect. Descending facilitation from the ACC apparently relays at the RVM. Electrical stimulation in the RVM produces a biphasic modulatory effect, showing facilitation at low intensities and inhibition at higher intensities. The present study provides evidence that activation of mGluRs within the ACC can facilitate spinal nociception.
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PMID:Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. 1083 58


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