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)

Activation of kappa-opioid receptors in the rostral ventral medulla has been reported to attenuate analgesia induced by activation of mu-opioid receptors in the periaqueductal gray matter. Previous studies have suggested that the cells associated with this effect might contain serotonin. In the present study, we investigated the relationship of the cloned kappa-opioid receptor to spinally projecting neurons immunoreactive for serotonin or GABA. This was done by employing two-color immunofluorescence in combination with retrograde tract-tracing using Fluoro-Gold. In the rostral ventral medulla, neurons triple-labeled for the cloned kappa-opioid receptor, serotonin and Fluoro-Gold were observed; neurons double-labeled for the cloned kappa-opioid receptor and serotonin, or single-labeled for the cloned kappa-opioid receptor or for serotonin were also observed. In addition, cloned kappa-opioid receptor immunoreactivity was expressed in some cell profiles immunoreactive for GABA. The expression of the cloned kappa-opioid receptor in the spinal cord dorsal horn was not associated with processes immunoreactive for serotonin. Our findings suggest that kappa-opioid receptors in the rostral ventral medulla are positioned to directly control the activity of at least some serotonergic neurons projecting to the dorsal spinal cord. Thus, it appears possible that the anti-analgesic action resulting from microinjection of kappa-opioid agonists into the rostral ventral medulla is mediated, at least in part, by these neurons.
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PMID:Serotonergic and GABAergic neurons in the medial rostral ventral medulla express kappa-opioid receptor immunoreactivity. 1018 49

1. The in vitro hemisected spinal cord from young rat was used to investigate the mechanism of serotoninergic modulation of primary afferent-mediated synaptic transmission in the dorsal horn through activation of the 5-HT3 receptor. 2. Dorsal root-evoked excitatory post-synaptic potentials (DR-EPSPs) were recorded intracellularly from dorsal horn neurones. Extracellular recordings of the population primary afferent depolarization (PAD) and the dorsal root-evoked dorsal root reflex (DR-DRR) were made from segmental dorsal roots. 3. 5-Hydroxytryptamine (5-HT) and the selective 5-HT3 receptor agonist 1-(m-chloro-phenyl)-biguanide hydrochloride (m-ChPB) (10 and 50 microM) induced statistically significant reductions of the DR-EPSP amplitude (P<0.001) and duration (P<0.001) in the majority of dorsal horn neurones. The 5-HT3 receptor selective antagonists 3-Tropanyl-indole-3-carboxylate hydrochloride (Tropisetron, 10 microM) and N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazine-8-carboxamide (Y-25130, 10 microM) abolished m-ChPB-induced DR-EPSP attenuation and partially blocked the 5-HT effect. 4. m-ChPB (50 microM)-induced DR-EPSP amplitude and duration attenuation was retained in the presence of the GABA(A) receptor antagonist bicuculline (30 microM), the GABA(B) receptor antagonist saclofen (50 microM) and the opioid receptor antagonist naloxone (50 microM). 5. Both 5-HT and m-ChPB (10 and 50 microM) induced a PAD but the mean peak amplitude of 5-HT-induced PAD was significantly greater than PAD to m-ChPB (98.6+/-12 microV compared to 51.8+/-10 V for 50 microM of agonist, respectively). Tropisetron partially reduced 5-HT-induced PAD and abolished m-ChPB-induced PAD. 5-HT, but not m-ChPB, significantly (P<0.001) reduced the peak amplitude of the DR-DRR and this action of 5-HT was unaffected by Tropisetron or Y-25130. 6. These data provide experimental evidence for a putative cellular mechanism at the level of the dorsal horn for anti-nociceptive effects of 5-HT3 receptor activation. This 5-HT3-mediated modulation of sensory afferent transmission was evidently independent of inhibitory GABA- or opioid-dependent interneuronal pathways. The extent to which the 5-HT3 receptor could be involved in the operation of endogenous analgesia and sensory modulation by descending monoamine bulbo-spinal pathways is discussed.
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PMID:Modulation of afferent-evoked neurotransmission by 5-HT3 receptors in young rat dorsal horn neurones in vitro: a putative mechanism of 5-HT3 induced anti-nociception. 1043 90

We tested the hypothesis that noxious stimuli induce pain modulation by activation of supraspinal structures. We found that intense noxious stimuli (i.e., subdermal injection of capsaicin or paw immersion in hot water) induced profound attenuation of the jaw-opening reflex in the anesthetized rat; forepaw subdermal capsaicin also elevated the mechanical hindpaw-withdrawal threshold in the awake rat. These antinociceptive effects were blocked by previous injection of either a dopamine antagonist (flupentixol) or an opioid antagonist (naloxone) into the nucleus accumbens. Additional experiments in anesthetized animals showed that the antinociceptive effect of noxious stimulation by either capsaicin (>/=100 micrograms) or hindpaw immersion in hot water (>/=45 degrees C for 4 min) correlated with the intensity of the stimulus. The maximal antinociceptive effect of capsaicin was similar in magnitude to that of a high dose of morphine (10 mg/kg) injected subcutaneously. Injection of the GABA(A)-receptor agonist muscimol, but not naloxone, into the rostroventral medulla, a major component of descending pain modulation systems, blocked capsaicin-induced antinociception. Although it is widely thought that painful stimuli may induce analgesia by activating forebrain structures, this is the first demonstration that such a mechanism exists. Furthermore, this mechanism can be engaged by naturalistic stimuli in awake animals. These observations imply that painful stimuli might under certain conditions be rewarding.
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PMID:Pain-induced analgesia mediated by mesolimbic reward circuits. 1043 70

The ventrolateral portion of the periaqueductal gray (PAG) is one brain region in which ligands of the mu-opioid receptor (MOR) produce analgesia. In the PAG, MOR ligands are thought to act primarily on inhibitory [e.g., gamma-aminobutyric acidergic (GABAergic)] neurons to disinhibit PAG output rather than directly on medullary-projecting PAG neurons. In this study, the ultrastructural localization of MOR immunolabeling was examined with respect to either GABAergic PAG neurons or PAG projection neurons that were labeled retrogradely from the rostral ventromedial medulla. Immunoreactivity for MOR and GABA often coexisted within dendrites. Dual-labeled profiles accounted for subpopulations of dendrites containing immunoreactivity for either MOR (65 of 145 dendrites; 45%) or GABA (65 of 183 dendrites; 35%). In addition, nearly half of PAG neuronal profiles (148 of 344 profiles) that were labeled retrogradely from the ventromedial medulla contained MOR immunoreactivity. MOR was distributed equally among retrogradely labeled neuronal profiles in the lateral and ventrolateral columns of the caudal PAG. With respect to the presynaptic distribution of MOR, approximately half of MOR-immunolabeled axon terminals (35 of 69 terminals) also contained GABA. Some MOR and GABA dual-immunolabeled axon terminals contacted unlabeled dendrites (11 of 35 terminals), whereas others contacted GABA-immunoreactive dendrites (15 of 35 terminals). Furthermore, axon terminals synapsing on medullary-projecting PAG neurons sometimes contained immunoreactivity for MOR. These data support the model that MOR ligands can act by inhibiting GABAergic neurons, but they also provide evidence that MOR ligands may act directly on PAG output neurons. In addition, MOR at presynaptic sites could affect both GABAergic neurons and output neurons. Thus, the disinhibitory model represents only partially the potential mechanisms by which MOR ligands can modulate output of the PAG.
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PMID:Presynaptic and postsynaptic relations of mu-opioid receptors to gamma-aminobutyric acid-immunoreactive and medullary-projecting periaqueductal gray neurons. 1074 19

1. mu-Opioid receptor agonists mediate their central analgesic effects by actions on neurons within brain regions such as the mid-brain periaqueductal grey (PAG). Within the PAG, mu-opioid receptor-mediated analgesia results from inhibition of GABAergic influences on output projection neurons. We have established that mu-opioid receptor activation in the PAG causes a presynaptic inhibition of GABA release that is mediated by activation of a voltage-dependent K+ channel via 12-lipoxygenase (LOX) metabolites of arachidonic acid. 2. At a cellular level, mu-opioid agonists have also been shown to open inwardly rectifying K+ channels, close voltage-gated Ca2+ channels and presynaptically inhibit glutamatergic synaptic transmission in the PAG. 3. The mu-opioid receptor-mediated presynaptic inhibition of GABAergic transmission was abolished by phospholipase A2 inhibitors and non-specific LOX and specific 12-LOX inhibitors. Cyclo-oxygenase (COX) and specific 5-LOX inhibitors did not reduce the inhibitory effects of mu-opioid agonists. 4. The opioid actions on GABAergic transmission were mimicked by arachidonic acid and 12-LOX metabolites, but not 5-LOX metabolites. The efficacy of mu-opioids was enhanced synergistically by treatment of PAG neurons with inhibitors of the other major enzymes responsible for arachidonic acid metabolism, COX and 5-LOX. 5. These results explain a previously described analgesic action of COX inhibitors in the central nervous system that was both independent of prostanoid release and inhibited by opioid receptor antagonists and they also explain the synergistic interaction of opioids with COX inhibitors. These findings also suggest new avenues for the development of centrally active analgesic agents involving combinations of lowered doses of opioids and specific 5-LOX inhibitors.
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PMID:Cellular actions of opioids and other analgesics: implications for synergism in pain relief. 1087 10

The endogenous opioid neurotransmitter beta-endorphin (beta-END), a product of the proopiomelanocortin (POMC) gene, is strongly implicated in the control of the female reproductive cycle, stress responses, and antinociception. Using selective gene targeting, we have generated a strain of mice that do not express any beta-END. These mice exhibit both normal reproduction and normal basal and stress-induced hypothalamic-pituitary-axis activity, but exhibit a significantly attenuated opioid-mediated stress-induced analgesia. To further understand the cellular bases of these responses, we have studied mediobasal hypothalamic (MBH) neurons, including POMC neurons, using whole-cell patch recording in an in vitro slice preparation. Twenty-seven MBH cells were recorded in wild-type and 25 MBH cells were recorded in beta-END knockout mice. Neurons from both genotypes showed a significant positive correlation between DAMGO concentration (from 30 nM to 10 microM) and the induced outward K(+) current. The genotypes did not differ, however, in either the DAMGO-induced maximum outward current response or EC(50), or for the maximal response to the GABA(B) agonist baclofen. Furthermore, quantitative receptor autoradiography utilizing (3)H-DAMGO did not reveal any differences in total mu-opioid receptor binding between genotypes. Therefore, we conclude that the complete absence of beta-END throughout development did not alter either the expression of mu-opioid receptors or their coupling to K(+) channels in MBH neurons.
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PMID:Effect of the mu-opioid agonist DAMGO on medial basal hypothalamic neurons in beta-endorphin knockout mice. 1107 Apr 24

The neural mechanisms involved in post-ictal analgesia remain to be elucidated. Pentylenetetrazol (PTZ) is used experimentally to induce seizure in animal subjects. This non-competitive antagonist blocks GABA-mediated Cl(-) flux. The aim of this work is to study the neurochemical basis of the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test, in eight rats per group. Convulsions were followed by significant increase in the tail-flick latencies (TFL), at least for 30 min of the post-ictal period. Peripheral administration of naloxone (5 mg/kg and 10 mg/kg), atropine (1 mg/kg and 5 mg/kg), methysergide (1 mg/kg and 5 mg/kg) and ketanserine (1 mg/kg and 2 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls. However, while naloxone antagonized analgesia 15 and 25 min post convulsions, the other drugs caused a blockade of the post-ictal analgesia in a relatively greater period of time. These results indicate that endogenous opioids, serotonin and acetylcholine may be involved in post-ictal analgesia.
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PMID:Post-ictal analgesia: involvement of opioid, serotoninergic and cholinergic mechanisms. 1115 Apr 91

Using the latency for tail-flick after thermal stimulation we have assessed the effects of alpha-, gamma(1)- and gamma(2)-MSH on nociceptive threshold in the mice. Intracisternal injections of gamma(2)-MSH induced a distinct analgesia, while gamma(1)-MSH in the same doses gave only a minor analgesia. Intracisternal alpha-MSH instead gave a short-term hyperalgesia. The effect of gamma(2)-MSH was not blocked by any of the MC(4)/MC(3)receptor antagonist HS014, naloxone or by the prior intracisternal administrations of gamma(1)-MSH. However, the gamma(2)-MSH analgesic response was completely attenuated by treating animals with the GABA(A)antagonist bicuculline. The gamma(2)-MSH analgesic effect was moreover additive to the analgesia afforded by muscimol and ethanol, but not to that afforded by diazepam. In addition both gamma(1)- and gamma(2)-MSH induced moderate catalepsy, but could at the same time attenuate haloperidol induced catalepsia. We conclude that gamma(2)-MSH mediates a central analgesic effect via GABA-receptor dependent pathway that is distinct from melanocortic- and opioid-receptors. Moreover, the mechanism for gamma(2)-MSH's analgesic effect appears to be distinct from that causing moderate catalepsia by gamma-MSH's.
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PMID:The gamma(2)-MSH peptide mediates a central analgesic effect via a GABA-ergic mechanism that is independent from activation of melanocortin receptors. 1134 10

Pentylenetetrazol (PTZ), a non-competitive antagonist that blocks GABA-mediated Cl(-) flux, was used in the present work to induce seizures in animals. The aim of this work is to study the neurochemical basis of the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test, in eight rats per group. Convulsions were followed by significative increase in the tail-flick latencies (TFL), for at least 120 min of the post-ictal period. Peripheral administration of naltrexone (5 mg/kg, 10 mg/kg and 20 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls. These data were corroborated with peripheral administration of naloxonazine (10 mg/kg and 20 mg/kg), a mu(1)-opioid blocker, in the same doses used for non-specific antagonist. These results indicate that endogenous opioids may be involved in the post-ictal analgesia. The involvement of mu(1)-opioid receptor was also considered.
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PMID:Opioid neurotransmission in the post-ictal analgesia: involvement of mu(1)-opioid receptor. 1138 5

Improgan is the prototype drug from a new class of non-opioid analgesics chemically related to histamine and histamine antagonists, but the mechanism of action of these compounds has not been identified. Because several classes of analgesics act in the brain by reducing GABAergic inhibition of endogenous pain-relieving circuits, and because the activity of these substances is abolished by the GABA(A) agonist muscimol, the present study assessed the effects of muscimol on improgan antinociception in rats. Intracerebroventricular (icv) improgan (80 microg) and morphine (20 microg) both induced 80-100% of maximal analgesic responses on the tail flick test 10 to 30 min later. However, muscimol pretreatment (0.5 microg, icv) completely eliminated the antinociceptive activity of both compounds. Since improgan in vitro lacks activity at opioid and GABA(A) receptors, these findings: 1) confirm earlier literature showing that muscimol inhibits morphine analgesia, and 2) suggest that improgan activates a supraspinal, descending analgesic pathway, possibly via inhibition of GABAergic transmission. Since muscimol is the first compound discovered which inhibits improgan analgesia, muscimol will be a useful tool for the further characterization of this new class of pain-relieving substances.
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PMID:Significance of GABAergic systems in the action of improgan, a non-opioid analgesic. 1140 Sep 17


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