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Neuro–Endocrine–Immune Dysfunction in the Chronic Pain Patient
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Opioids play a role in modulating pain throughout the CNS. While opiates are presumed analogues to endogenous opioids such as enkephalin, dynorphin, and β-endorphin, there is little evidence showing the role played by these endogenous opioids in the pain system. Opioids bind to the µ-opioid receptor primarily on the C fiber afferents (located in the superficial dorsal horn and cell bodies of the deeper dorsal horn neurons) inhibiting neuronal discharge. Aβ fibers are also present here but are not typically affected by opioids. The pre-synaptic opioid effect works primarily by preventing the opening of Ca2+ channels which limits peptide neurotransmitter release (such as SP). Post-synaptic neurons experience K+ channel activation which results in hyperpolarization.28
Electrically excitable nerve elements: excitation sites in peripheral and central stimulation
Published in Hans O Lüders, Deep Brain Stimulation and Epilepsy, 2020
The results presented in this chapter highlight differences in the effects of stimulus polarity and sites of excitation in peripheral and central stimulation. During stimulation of peripheral nerves the threshold difference between cathodic and anodic stimuli arises due to a shift in the site of excitation from the most polarized portion of the axon to the flanking regions polarized by ‘virtual electrodes’. During CNS stimulation action potentials are initiated in the axons of local cells, even for electrodes positioned over the cell body. The threshold difference between cathodic and anodic stimuli arises because of differences in the mode of activation. Anodic stimuli cause depolarization of the axon and excitation via a ‘virtual cathode’, as occurs during PNS stimulation. Cathodic stimuli cause hyperpolarization at the site of excitation and the action potential is initiated during repolarization. This difference in excitation mechanism was exploited to design novel asymmetrical biphasic stimulus pulses that increased the selectivity between excitation of local cells and axons of passage.
Other Relaxing Substances Released by the Endothelium
Published in Thomas F. Lüscher, Paul M. Vanhoutte, The Endothelium: Modulator of Cardiovascular Function, 2020
Thomas F. Lüscher, Paul M. Vanhoutte
The hyperpolarizing effect, at least in canine coronary smooth muscle, requires the activity of the electrogenic Na+-K+ pump as it can be prevented by ouabain.301 By contrast, in the ear artery of the rabbit, acetylcholine-induced endothelium-dependent hyperpolarization is not inhibited by the glycoside.1216 The amplitude of the change in membrane potential is enhanced in low [K]0 solutions and reduced in high [K]0 solutions;164 the ionic conductance of the membrane is augmented during the hyperpolarization.164,659 The latter is accompanied by an increase in 86Rb efflux rate, a time course comparable to that of the electrical changes.1228 Acetylcholine produces a transient increase in the K+ efflux which parallels with the time course of the hyperpolarization.165 These findings support the interpretation that the hyperpolarization is mediated through an increase in potassium conductance.99,164,659,1229
Hyperoside ameliorates cerebral ischaemic–reperfusion injury by opening the TRPV4 channel in vivo through the IP3-PKC signalling pathway
Published in Pharmaceutical Biology, 2023
Lei Shi, Chenchen Jiang, Hanghang Xu, Jiangping Wu, Jiajun Lu, Yuxiang He, Xiuyun Yin, Zhuo Chen, Di Cao, Xuebin Shen, Xuefeng Hou, Jun Han
First, the rats were sacrificed by CO2 asphyxiation. Then, cerebral vessels were carefully excised from rats under an inverted microscope, fixed in a 10 mL silica gel slot with an average pressure of 85 mmHg, bubbled with PSS containing 95% O2 and 5% CO2, and incubated at a temperature of 37 °C for 1 h. Microelectrodes for the detection of intracellular membrane potential (Em) were applied to vascular endothelial smooth muscle cells (VSMCs) of the CBA. A glass microelectrode (40–80 MΩ, filled with 3 mol/L KCl) was inserted into each VSMC to measure the trends in the intracellular membrane potential (Em) value. The potential difference and interference (50 Hz) were recorded using a conventional high-impedance amplifier and selectively moved aside. The values of Em were monitored and analysed using a MacLab system connected to Chart 5 software. Hyperpolarization of VSMC membranes was recorded as soon as the negative resting membrane potential increased evidently (Petersen 2017).
Moringa oleifera seed ethanol extract and its active component kaempferol potentiate pentobarbital-induced sleeping behaviours in mice via a GABAergic mechanism
Published in Pharmaceutical Biology, 2022
Wei-Liang Liu, Bai-Fen Wu, Jian-Hua Shang, Xue-Feng Wang, Yun-Li Zhao, Ai-Xiang Huang
Several studies have demonstrated that in the physiological state, the extracellular and intracellular chloride concentrations should be ∼130 mmol/L (mM) and 10 mM, respectively (Winsky-Sommerer 2009). When GABA or GABAA receptor agonists bind with GABAA receptor, Cl– channels are open and the Cl– influx flows into the cell along the concentration gradient. Furthermore, the cell membrane hyperpolarization exerted the sedative, antianxiety and antiepileptic effects (Jonsson Fagerlund et al. 2010). MQAE, which is a Cl–-SFLUOP, is used for detecting intracellular Cl–. When it interacts with Cl-, its FLUO is quenched instantaneously (Yan et al. 2015). Thus, it acts as a FLUO indicator in an ion concentration-dependent manner.
Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain
Published in Expert Opinion on Pharmacotherapy, 2022
Qiu Qiu, Joshua CJ Chew, Michael G Irwin
All opioid receptors are inhibitory G-protein coupled receptors (GPCRs). Although the clinical effects can differ, the signaling mechanism of inhibitory GPCRs are the same. When an opioid agonist binds to the receptor, the receptor complex undergoes a conformational change. The α subunit exchanges its bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP). Subsequently, the α-GTP and βγ subunit dissociate and proceed to interact with effector proteins such as adenylate cyclase and modulate ion channels. With inhibitory GPCRs, agonism causes the inhibition of adenylyl cyclase, leading to the reduction in formation of intracellular adenosine monophosphate (cAMP). The βγ subunit activates G protein-coupled inwardly rectifying potassium channels and inhibits voltage gated calcium channels. This results in hyperpolarisation and decreased neurotransmitter release. Agonism also leads to the recruitment of GPCR kinase which phosphorylates the GPCR. The phosphorylated GPCR subsequently binds β-arrestin, and this family of cytosolic proteins has been implicated in causing respiratory depression, tolerance and constipation. Phosporylated GPCRs can be recycled to the cell membrane or undergo lysosomal degradation [12–15] (Figure 1). Reduced available receptors via this mechanism is how the receptor is negatively regulated, and leads to decreased sensitivity and tolerance [16].