Evidence that disinhibition of brain stem neurones contributes to morphine analgesia

Fields, Howard L.; Vanegas, Horacio; Hentall, Ian D.; Zorman, Greg

doi:10.1038/306684a0

Cited by 234 publications

(109 citation statements)

References 11 publications

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“…The first supraspinal site identified as participating in pain modulation was the ventrolateral periaqueductal gray matter (vlPAG; Yeung et al, 1977). Subsequently, the rostral ventromedial medulla (RVM) was found to modulate pain transmission (Fields et al, 1983;Mitchell et al, 1998). The analgesic functions of the vlPAG and the RVM are partially mediated by descending serotoninergic and noradrenergic systems (Brodie and Proudfit, 1984;Barbaro et al, 1985;Jensen and Yaksh, 1986).…”

Section: Indexing Termsmentioning

confidence: 99%

Role of endogenous sleep‐wake and analgesic systems in anesthesia

Lü

Nelson

Franks

et al. 2008

J of Comparative Neurology

216

190

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Classical anesthetics of the γ-aminobutyric acid type A receptor (GABA A )-enhancing class (e.g., pentobarbital, chloral hydrate, muscimol, and ethanol) produce analgesia and unconsciousness (sedation). Dissociative anesthetics that antagonize the N-methyl-D-aspartate (NMDA) receptor (e.g., ketamine, MK-801, dextromethorphan, and phencyclidine) produce analgesia but do not induce complete loss of consciousness. To understand the mechanisms underlying loss of consciousness and analgesia induced by general anesthetics, we examined the patterns of expression of c-Fos protein in the brain and correlated these with physiological effects of systemically administering GABAergic agents and ketamine at dosages used clinically for anesthesia in rats. We found that GABAergic agents produced predominantly delta activity in the electroencephalogram (EEG) and sedation. In contrast, anesthetic doses of ketamine induced sedation, followed by active arousal behaviors, and produced a faster EEG in the theta range. Consistent with its behavioral effects, ketamine induced Fos expression in cholinergic, monoaminergic, and orexinergic arousal systems and completely suppressed Fos immunoreactivity in the sleep-promoting ventrolateral preoptic nucleus (VLPO). In contrast, GABAergic agents suppressed Fos in the same arousal-promoting systems but increased the number of Fosimmunoreactive neurons in the VLPO compared with waking control animals. All anesthetics tested induced Fos in the spinally projecting noradrenergic A5-7 groups. 6-hydroxydopamine lesions of the A5-7 groups or ibotenic acid lesions of the ventrolateral periaqueductal gray matter (vlPAG) attenuated antinociceptive responses to noxious thermal stimulation (tail-flick test) by both types of anesthetics. We hypothesize that neural substrates of sleep-wake behavior are engaged by low-dose sedative anesthetics and that the mesopontine descending noradrenergic cell groups contribute to the analgesic effects of both NMDA receptor antagonists and GABA A receptor-enhancing anesthetics. Anesthetics that modulate the γ-aminobutyric acid type A receptor (GABA A ; by direct gating of the Cl channel or by potentiating the effects GABA; hereafter referred to as GABA A agents) induce both analgesia and loss of consciousness (sedation) and are associated with a slow-wave electroencephalogram (EEG) pattern and depressed CNS function (for review see Sloan, 1998). In contrast, anesthetics that act by antagonizing Nmethyl-D-aspartate (NMDA) receptors (e.g., ketamine, MK-801, phencyclidine, dextromethorphan, and nitrous oxide) produce analgesia but also preserve some aspects of consciousness (dissociative anesthesia). These NMDA receptor antagonist anesthetics are associated, especially at subanesthetic doses, with a fast, theta-range EEG (5-7 Hz) and maintenance of sympathetic tone (Yamamura et al., 1981;Carruba et al., 1987;Marquis et al., 1989;Sagratella et al., 1992; Mattia and Moreton, 1996). There is an increase in the EEG delta power (<4 Hz) during subsequent episodes of slee...

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Section: Indexing Termsmentioning

confidence: 99%

Role of endogenous sleep‐wake and analgesic systems in anesthesia

Lü

Nelson

Franks

et al. 2008

J of Comparative Neurology

216

190

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“…Both Off-and On-cells are found in regions of the medulla having the lowest threshold for inhibition of the TF by electrical stimulation (Fields et al, 1983a), and a significant proportion of both cell classes projects to the spinal cord (Vanegas et al, 1984a). Furthermore, the activity of both On-and Off-cells is altered by systemically administered morphine given in doses sufficient to inhibit the TF: Off-cell activity is increased (Fields et al, 1983b), while that of On-cells is decreased (Barbaro et al, 1986).…”

mentioning

confidence: 98%

Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray

Heinricher¹,

Cheng²,

Fields³

1987

J. Neurosci.

109

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The midbrain periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM) are important links in a neuronal network that modulates nociceptive transmission. In the RVM, 2 classes of cells have been identified that show changes in activity at the time of the tail-flick response (TF) elicited by noxious heat (Fields et al., 1983a). We now report that neurons in the PAG region also show changes in activity related to TF. Extracellular recordings were made from the PAG and the ventrally adjacent tegmentum at sites from which it was possible to inhibit TF using stimulating currents of 10 microA or less. Cell activity, time of TF occurrence, and tail temperature were recorded during 5 repetitions of the heat stimulus. Periresponse and peristimulus histograms were plotted with reference to the TF and tail temperature, respectively. A significant number of neurons in the PAG region showed changes in activity that preceded the TF. “Midbrain On- cells” (13.6% of the sample) displayed an abrupt increase in firing just prior to the TF. “Midbrain Off-cells” (4.4%) paused just prior to the TF. The remaining neurons (241 of 294, or 82%) did not exhibit changes in firing prior to the TF. Thus, cells with changes in activity related to the TF are present in the PAG region as well as in the RVM. The PAG has a large projection to the RVM, and microinjection of morphine in the PAG increases activity of RVM Off-cells and decreases that of RVM On-cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Several different types of NRM neurons have been characterized in vivo and in vitro, and as shown in previous studies, each type of NRM neuron can exhibit a distinct inhibitory or facilitatory effect on spinal pain transmission (Fields et al, 1983;Pan et al, 1990;Fields, 2004). One type of NRM neurons, defined by its inhibitory response to opioid analgesics as agonists of the m-opioid receptor (MOR) and by its membrane expression of functional MOR, is thought to facilitate spinal pain transmission (Pan et al, 1997;Fields, 2004).…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K⁺–Cl^– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation

Zhang

Wang

et al. 2013

Mol Pharmacol

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Chronic pain is thought to be partly caused by a loss of GABAergic inhibition and resultant neuronal hyperactivation in the central pain-modulating system, but the underlying mechanisms for pain-modulating neurons in the brain are unclear. In this study, we investigated the cellular mechanisms for activation of brainstem descending pain facilitation in rats under persistent pain conditions. In the nucleus raphe magnus (NRM), a critical relay in the brain's descending pain-modulating system, persistent inflammatory pain induced by complete Freund's adjuvant decreased the protein level of K 1 -Cl 2 cotransporter (KCC2) in both total and synaptosomal preparations. Persistent pain also shifted the equilibrium potential of GABAergic inhibitory postsynaptic current (E IPSC ) to a more positive level and increased the firing of evoked action potentials selectively in m-opioid receptor (MOR)-expressing NRM neurons, but not in MOR-lacking NRM neurons. Microinjection of brain-derived neurotrophic factor (BDNF) into the NRM inhibited the KCC2 protein level in the NRM, and both BDNF administration and KCC2 inhibition by furosemide mimicked the pain-induced effects on E IPSC and excitability in MOR-expressing neurons. Furthermore, inhibiting BDNF signaling by NRM infusion of tyrosine receptor kinase B-IgG or blocking KCC2 with furosemide prevented these pain effects in MOR-expressing neurons. These findings demonstrate a cellular mechanism by which the hyperactivity of NRM MOR-expressing neurons, presumably responsible for descending pain facilitation, contributes to pain sensitization through the signaling cascade of BDNF-KCC2-GABA impairment in the development of chronic pain.

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Evidence that disinhibition of brain stem neurones contributes to morphine analgesia

Cited by 234 publications

References 11 publications

Role of endogenous sleep‐wake and analgesic systems in anesthesia

Role of endogenous sleep‐wake and analgesic systems in anesthesia

Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray

Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K⁺–Cl^– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation

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Evidence that disinhibition of brain stem neurones contributes to morphine analgesia

Cited by 234 publications

References 11 publications

Role of endogenous sleep‐wake and analgesic systems in anesthesia

Role of endogenous sleep‐wake and analgesic systems in anesthesia

Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray

Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K+–Cl– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation

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Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K⁺–Cl^– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation