UMLS:C0344307 - FACTA Search

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Query: UMLS:C0344307 (analgesia)
28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analgesia results when opiates are microinjected into the rostral ventromedial medulla (RVM). This region, which includes the nucleus raphe magnus and the adjacent reticular formation, is rich in immunoreactive enkephalin-containing neurones and terminals, and contains neurones that project to the spinal cord dorsal horn where they inhibit identified nociceptive spinothalamic tract neurones. Although opiates have previously been reported either to excite or inhibit RVM cells, the possibility of an opiate effect being consistent within a physiologically defined subclass has not been examined. Recently we described a class of neurone in the RVM (the off-cell) that abruptly pauses just before a heat-evoked tail-flick reflex. If off-cells are made to fire continuously by direct electrical stimulation of the RVM, the tail-flick reflex does not occur. We report here that analgesic doses of morphine completely eliminate the pause in firing that precedes the tail-flick reflex. We propose that this disinhibition of off-cells in the RVM is a primary process contributing to opiate inhibition of nociceptor-induced reflexes.
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PMID:Evidence that disinhibition of brain stem neurones contributes to morphine analgesia. 665 68

Changes in responsiveness for the stinging reaction of honeybees fixed in a holder after receiving 3 electrical shocks delivered with 1 min interval, was registered and used as measurement for the effect of 2 microliter of different solutions injected. Every shock consisted of a train of pulses of 1 msec each, delivered for 2 sec at a frequency of 100 Hz. Injection of morphine-HCl (50 to 200 n-moles/bee) produced a dose dependent reduction of the honeybee stinging response to the electrical shocks. The morphine dose that produced a 50% inhibition of the response (D50) was 148 n-moles/bee (927 micrograms/g), i.e., a value far greater than that reported for vertebrates in behavioral test of analgesia. Naloxone 1.1 micrograms/g produces a significant reduction of morphine D50 effect and at 4-5 micrograms/g, a full disinhibition. Thus, whereas the D50 of morphine for honeybees is far greater than that for vertebrates, the doses of naloxone that antagonize morphine are similar for bees and vertebrates. Possible explanations of this difference are mentioned. Injections of met-enkephalin, leu-enkephalin, kyotorphin and (D-Ala2) methionine-enkephalinamide, given in doses of 200 n-moles/bee, an amount greater than that of the morphine D50, exhibited no effect on the stinging response.
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PMID:The stinging response of the honeybee: effects of morphine, naloxone and some opioid peptides. 665 18

1. Rat caudal periaqueductal grey (PAG) output neurones containing rhodamine microspheres, retrogradely transported from an injection site in the rostral ventromedial medulla (RVM), were visualized in brain slices and recorded from using whole-cell patch clamp techniques. 2. The specific GABAB receptor agonist baclofen (10 microM) produced an outward current or hyperpolarization in fifty out of fifty-six caudal PAG output neurones. In 44% of these baclofen-sensitive neurones, the opioid agonist methionine enkephalin (30 microM) also produced an outward current or hyperpolarization. The opioid current reversed polarity at -104 mV and could also be produced by DAMGO, an agonist selective for the mu-subtype of opioid receptor. 3. Opioid-responding output neurones were not distributed uniformly in the caudal PAG. In horizontal slices containing lateral PAG, 56% of output neurones were inhibited by opioids, as compared with only 14% of the output neurones in slices containing ventrolateral PAG. 4. These observations are consistent with opioid disinhibition of ventrolateral PAG neurones projecting to the RVM as the predominant mechanism underlying opioid-induced analgesia in the PAG. The role of opioid receptors found on a major proportion of the output neurones in the lateral PAG remains to be established, but is assumed not be related to modulation of nociceptive function.
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PMID:Opioid inhibition of rat periaqueductal grey neurones with identified projections to rostral ventromedial medulla in vitro. 882 Nov 37

1. The actions of opioids on synaptic transmission in rat periaqueductal grey (PAG) neurones were examined using whole-cell patch-clamp recordings in brain slices. 2. Methionine enkephalin (ME; 10 microM) inhibited evoked GABAergic inhibitory postsynaptic currents (IPSCs) by 57%, non-NMDA excitatory postsynaptic currents (EPSCs) by 60%, and NMDA EPSCs by 43% in PAG neurones. This inhibition was associated with an increase in paired-pulse facilitation, was mimicked by the mu-agonist DAMGO (1-3 microM) and abolished by naloxone (1 microM). Neither the kappa-agonist U69593 (1-3 microM), nor the delta-agonist DPDPE (3-10 microM) had any specific actions on evoked PSCs. 3. ME decreased the frequency of spontaneous miniature, action potential-independent postsynaptic currents (mIPSCs by 65%, mEPSCs by 54%) in all PAG neurones, but had no effect on their amplitude distributions. The reduction in mIPSC frequency persisted in nominally Ca(2+)-free, high-Mg2+ (10 mM) solutions, which also contained Cd2+ (100 microM), or Ba2+ (10 mM). Opioid inhibition of mIPSC frequency is unlikely to be mediated by presynaptic Ca2+ or K+ conductances which are sensitive to extracellular Cd2+ or Ba2+. 4. In a subpopulation of PAG neurones, ME increased a Ba(2+)-sensitive K+ conductance at potentials below -97 mV. Opioids inhibited both GABAergic and glutamatergic synaptic transmission in all PAG neurones, independent of any postsynaptic opioid sensitivity. 5. These observations are consistent with, but only partially support, the opioid disinhibition model of PAG-induced analgesia. mu-Opioids also have the potential to modulate the behavioural and autonomic functions of the PAG via modulation of both inhibitory and excitatory presynaptic mechanisms, as well as postsynaptic mechanisms.
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PMID:Presynaptic inhibitory action of opioids on synaptic transmission in the rat periaqueductal grey in vitro. 903 93

The analgesic actions of opioids are in large part mediated by activation of brainstem pain modulating neurons that depress nociceptive transmission at the level of the dorsal horn. The present study was designed to characterize the contribution of N-methyl-D-aspartate (NMDA)- and non-NMDA-mediated excitatory transmission within the rostral ventromedial medulla (RVM) to the activation of brainstem inhibitory output neurons and analgesia produced by systemic morphine administration. The NMDA receptor antagonist D-2-amino-5-phosophonopentanoic acid (AP5), the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) or saline was infused into the RVM of lightly anesthetized rats while recording the activity of identified pain modulating neurons: 'off-cells', thought to inhibit nociceptive transmission, and 'on-cells', thought to facilitate nociception. Nociceptive responsiveness (tail flick latency) was not affected by either antagonist. AP5, but not CNQX, attenuated or blocked activation and disinhibition of off-cells and the antinociception produced by systemically administered morphine. Reflex-related discharge of on-cells was unaffected by AP5, but significantly attenuated by CNQX. The present results highlight two important aspects of RVM pain modulatory circuits. First, morphine given systemically produces its analgesic effect at least in part by recruiting an NMDA-mediated excitatory process to activate off-cells within the RVM. This excitatory process may play a role in the analgesic synergy produced by simultaneous mu-opioid activation at different levels of the neuraxis. Second, reflex-related activation of on-cells is mediated by a non-NMDA receptor, and this activation does not appear to play a significant role in regulating reflex responses to acute noxious stimuli. Excitatory amino acid-mediated excitation thus has at least two distinct roles within the RVM, activating off-cells and on-cells under different conditions.
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PMID:Activation of brainstem N-methyl-D-aspartate receptors is required for the analgesic actions of morphine given systemically. 1132 34

In the ventrolateral periaqueductal gray (PAG), activation of excitatory output neurons projecting monosynaptically to OFF cells in the rostral ventromedial medulla (RVM) causes antinociceptive responses and is under the control of cannabinoid receptor type-1 (CB1) and vanilloid transient receptor potential vanilloid type 1 (TRPV1) receptors. We studied in healthy rats the effect of elevation of PAG endocannabinoid [anandamide and 2-arachidonoylglycerol (2-AG)] levels produced by intra-PAG injections of the inhibitor of fatty acid amide hydrolase URB597 [cyclohexylcarbamic acid-3'-carbamoyl-biphenyl-3-yl ester] on 1) nociception in the "plantar test" and 2) spontaneous and tail-flick-related activities of RVM neurons. Depending on the dose or time elapsed since administration, URB597 (0.5-2.5 nmol/rat) either suppressed or increased thermal nociception via TRPV1 or CB1 receptors, respectively. TRPV1 or cannabinoid receptor agonists capsaicin (6 nmol) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN55,212-2 (4 nmol)] also suppressed or enhanced nociception, respectively. URB597 dose dependently enhanced PAG anandamide and 2-AG levels, with probable subsequent activation of TRPV1/CB1 receptors and only CB1 receptors, respectively. The TRPV1-mediated antinociception and CB1-mediated nociception caused by URB597 correlated with enhanced or reduced activity of RVM OFF cells, suggesting that these effects occur via stimulation or inhibition of excitatory PAG output neurons, respectively. Accordingly, several ventrolateral PAG neurons were found by immunohistochemistry to coexpress TRPV1 and CB1 receptors. Finally, at the highest doses tested, URB597 (4 nmol/rat) and, as previously reported, WIN55,212-2 (25-100 nmol) also caused CB(1)-mediated analgesia, correlating with stimulation (possibly disinhibition) of RVM OFF cells. Thus, endocannabinoids affect the descending pathways of pain control by acting at either CB1 or TRPV1 receptors in healthy rats.
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PMID:Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. 1628 79

Although glycine receptor Cl- channels (GlyRs) have long been known to mediate inhibitory neurotransmission onto spinal nociceptive neurons, their therapeutic potential for peripheral analgesia has received little attention. However, it has been shown that alpha3-subunit-containing GlyRs are concentrated into regions of the spinal cord dorsal horn where nociceptive afferents terminate. Furthermore, inflammatory mediators specifically inhibit alpha3-containing GlyRs, and deletion of the murine alpha3 gene confers insensitivity to chronic inflammatory pain. This strongly implicates GlyRs in the inflammation-mediated disinhibition of centrally projecting nociceptive neurons. Future therapies aimed at specifically increasing current flux through alpha3-containing GlyRs may prove effective in providing analgesia.
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PMID:Glycine receptors: a new therapeutic target in pain pathways. 1642 71

We review previously published data, and present some new data, indicating that spinal application of neuropeptide Y (NPY) reduces behavioral and neurophysiological signs of acute and chronic pain. In models of acute pain, early behavioral studies showed that spinal (intrathecal) administration of NPY and Y2 receptor agonists decrease thermal nociception. Subsequent neurophysiological studies indicated that Y2-mediated inhibition of excitatory neurotransmitter release from primary afferent terminals in the substantia gelatinosa may contribute to the antinociceptive actions of NPY. As with acute pain, NPY reduced behavioral signs of inflammatory pain such as mechanical allodynia and thermal hyperalgesia; however, receptor antagonist studies indicate an important contribution of spinal Y1 rather than Y2 receptors. Interestingly, Y1 agonists suppress inhibitory synaptic events in dorsal horn neurons (indeed, well known mu-opioid analgesic drugs produce similar cellular actions). To resolve the behavioral and neurophysiological data, we propose that NPY/Y1 inhibits the spinal release of inhibitory neurotransmitters (GABA and glycine) onto inhibitory neurons, e.g. disinhibition of pain inhibition, resulting in hyporeflexia. The above mechanisms of Y1- and Y2-mediated analgesia may also operate in the setting of peripheral nerve injury, and new data indicate that NPY dose-dependently inhibits behavioral signs of neuropathic pain. Indeed, neurophysiological studies indicate that Y2-mediated inhibition of Ca(2+) channel currents in dorsal root ganglion neurons is actually increased after axotomy. We conclude that spinal delivery of Y1 agonists may be of use in the treatment of chronic inflammatory pain, and that the use of Y1 and Y2 agonists in neuropathic pain warrants further consideration.
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PMID:Spinal mechanisms of NPY analgesia. 1719 6

Episodes of paroxysmal sympathetic hyperactivity, sometimes referred to as autonomic storms, are not uncommon in patients with severe traumatic brain injury. Their distinctive characteristics include fever, tachycardia, hypertension, tachypnea, hyperhidrosis, and dystonic posturing. The episodes may be induced by stimulation or may occur spontaneously. Their pathophysiology has not been fully elucidated, but the manifestations clearly indicate activation or disinhibition of sympathoexcitatory areas. These spells are often confused with seizures, leading to unnecessary treatment with antiepileptic drugs. General principles in the management of paroxysmal sympathetic hyperactivity include adequate hydration, exclusion of mimicking conditions (infection, pulmonary embolism, hydrocephalus, epilepsy), effective analgesia, and avoidance of triggers, when identified. The most useful pharmacologic agents are morphine sulfate and nonselective beta-blockers (eg, propranolol). Intrathecal baclofen may be effective in refractory cases. Bromocriptine and clonidine are helpful in some patients, but their efficacy is less consistent. Early recognition and adequate treatment of paroxysmal sympathetic hyperactivity is important to avoid prolongation of the patient's stay in the intensive care unit and to enable recovering patients to participate without restrictions in rehabilitation therapy.
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PMID:Treatment of paroxysmal sympathetic hyperactivity. 1833 37

Modern concepts of pain therapy involve neuronal mechanisms of endogenous analgesia. Recent animal experiments have provided new insights into the anatomy, physiology and neurobiology of endogenous antinociception. We have shown that antinociception can be maximally activated by disinhibition-and not by direct electrical or chemical excitation-in the midbrain periaqueductal grey matter. This disinhibition is a likely mechanism of opioid analgesia. 'Purely analgesic' stimulation produces a very distinct pattern of activated neurons within the periaqueductal grey matter and other areas of the brain stem, as revealed by the expression of the nuclear c-FOS protein as a cellular marker of activated neurons. In addition to the classic segmental and supraspinal, descending inhibition, a third principle of endogenous antinociception exists: the propriospinal, intersegmental inhibition of nociceptive spinal dorsal horn neurons. Propriospinal antinociception partly mediates the descending inhibition from the brain stem and can be activated by conditioning heterosegmental noxious stimuli, thus possibly contributing to analgesia by counterirritation. In addition to the fast synaptic transmission mediated by classic neurotransmitters, the extrasynaptic transmission of chemical signals such as neuropeptides may play an important role for long-term effects following intense noxious stimulation. The controlled superfusion of the dorsal cord with neuropeptides produces a similar distribution in the spinal cord to that of endogenously released neuropeptide. We have shown that extrasynaptic neuropeptides such as substance P may increase the excitability of nociceptive spinal dorsal horn neurons and may induce the expression of 'immediate-early genes' in dorsal horn neurons in vivo. Changes in gene expression following extrasynpatic spread of neuropeptides in the spinal cord may be involved in chronic pain syndromes after massive peripheral trauma. This hypothesis has led to the concept of pre-emptive analgesia. The available evidence suggests that the known systems of endogenous antinociception do not affect the endogenous release of neuropeptides in the spinal cord. All previous concepts of endogenous antinociception are based on changes in dischargerates of nociceptive neurons. Background activity in the absence of noxious stimulation was considered to be purely stochastic 'noise'. By the use of modern tools for the analysis of nonlinear dynamics in point processes we have, however, shown that background activity of most nociceptive spinal dorsal horn neurons is highly deterministic with a low degree of freedom. The high order in the discharges of these neurons is maintained, at least in part, by tonically active descending systems. Thus, the spinal shock syndrome seen in some species after acute spinalisation may result from the loss of order in spinal neuronal discharges normally provided by the brain. The use of modern methods in studies of the functional neuroanatomy, neurophysiology and neurobiology of endogenous antinociception may help in the achievement of better application of results from basic sciences to clinically relevant pain problems.
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PMID:[Endogenous analgesic mechanism: new concepts from functional neuroanatomy, neurophysiology, neurobiology and chaos research.]. 1841 89

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