Frankenstein Opioids + Pain CuntRoll

Although depression has a high rate of recurrence, no prior studies have established a method that could identify the warning signs of its recurrence.We collected digital data consisting of individual activity records such as location or mobility information ...

As is immediately obvious from my title, I use the neologism entheogen(ic) throughout this book, a new word proposed by a group of scholars including Dr. R. Gordon Wasson, Prof. Carl A. P. Ruck and me. As we know from personal experience that shamanic inebriants do not provoke "hallucinations" or "psychosis," and feel it incongruous to refer to traditional shamanic use of psychedelic plants (that word, pejorative for many, referring invariably to sixties' western drug use), we coined this new term in 1979 (Ruck et al. 1979). I outline thoroughly the histories of words for sacred plant drugs in Chapter 1, Note 1. I am happy to say, fourteen years after launching the neologism on its literary career, that the word has been accepted by the majority of experts in this field, and has appeared in print in at least seven languages. The term is not meant to specify a pharmacological class of drugs (some, for example, conceive of psychedelic as implying indole and phenethylamine drugs with an LSD- or mescaline-like effect); rather, it designates drugs which provoke ecstasy and have traditionally been used as shamanic or religious inebriants, as well as their active principles and artificial congeners. (page 15)

The rapidly expanding fields of molecular and cellular neurobiology are the newest frontiers of neuroscience. This book represents the continuing efforts of the Institute of Developmental Neuroscience and Aging (IDNA) to disseminate the most recent advances on the developing and aging nervous system at the molecular and cellular levels. A group of neuroscientists presented and discussed their findings at a recent IDNA conference held in Athens, Greece, June 15-18, 1988. This meeting was sponsored by the National Hellenic Research Foundation, FIDIA, the Ministry of Research and Technology, the Tourism Organization of Greece, and the National Institute of Child Health and Human Development, NIH. The Directors of the IDNA are grateful to the local committee, Drs. Eleni Fleischer, Costas Sekeris, Michael Alexis, Theony Valcana, and Elias Kouvelas, for their efforts in organizing this meeting and for their successful integration of science and culture for the participants. This volume provides a comprehensive overview of the information presented at this conference, including in-depth discussions of each topic by the participants. The chapters are grouped into five general categories which correspond to the subject areas covered during the meeting. These include: Gene and Phenotypic Expression, Growth Factors and Oncogenes, Cytoskeletal and Extracellular Molecules, Neurotransmitters and Hormones, and Molecular Aspects of Aging and Alzheimer's Disease. The section on Gene and Phenotypic Expression includes discussions of transient gene expression in the nervous system (Herschman), developmental regulation of myelin-associated genes (Gordon et al.

In previous studies, we showed that low (nM) concentrations of opioids prolong the action potential duration (APD) of many mouse dorsal root ganglion …

Etorphine elicits anomalous excitatory opioid effects on sensory neurons treated with GM1 ganglioside or pertussis toxin in contrast to its potent inhibitory effects on naive or chronic morphine-treated cells | Stanley M. Crain; Ke-Fei Shen | download | BookSC. Download books for free. Find books

Mouse sensory dorsal-root ganglion (DRG) neurons chronically exposed to 1 μM D-Ala2-D-Leu5-enkephalin (DADLE) for >1 week in culture become tolerant t…

Prolongation of the action potential duration of dorsal root ganglion (DRG) neurons by low (nM) concentrations of opioids occurs through activation of excitatory opioid receptors that are positively coupled via Gs regulatory protein to adenylate cyclase. Previous results suggested GM1 ganglioside to …

The mechanism of action of the dimeric enkephalin peptide, biphalin (Tyr-d-Ala-Gly-Phe-NH 2 ) 2 which was previously shown to have remarkable high antinociceptive potency and low dependence liability in vivo, has now been studied by electrophysiologic analyses of its effects on the action potential duration (APD) of nociceptive types of sensory dorsal root ganglion (DRG) neurons in culture. Acute application of biphalin (pM-μM) elicited only dose-dependent, naloxone-reversible inhibitory (APD-shortening) effects on DRG neurons. Furthermore, at pM concentrations that evoked little or no alteration of the APD of DRG neurons biphalin selectively antagonized excitatory (APD-prolonging) effects of low (fM-nM) concentrations of bimodally-acting μ and δ opioid agonists and unmasked potent inhibitory effects of these opioids. This dual opioid inhibitory-agonist/excitatory-antagonist property of biphalin is remarkably similar to that previously observed in studies of the ultra-potent opioid analgesic, etorphine on DRG neurons and in sharp contrast to the excitatory agonist action of most μ, δ and κ opioid alkaloids and peptides when tested at low (pM-nM) concentrations. Chronic treatment of DRG neurons with high (μM) concentrations of biphalin did not result in supersensitivity to the excitatory effects of naloxone nor in tolerance to opioid inhibition effects, in contrast to the excitatory opioid supersensitivity and tolerance that develop in chronic morphine- or DADLE-treated, but not chronic etorphine-treated, neurons. These studies on DRG neurons in vitro may help to account for the unexpectedly high antinociceptive potency and low dependence liability of biphalin as well as etorphine in vivo.

Background. Underlying mechanisms behind opioid-induced respiratory depression are not fully understood. The authors investigated changes in burst rate, intraburst firing frequency, membrane properties, as well as presynaptic and postsynaptic events of respiratory neurons in the isolated brainstem after administration of opioid receptor agonists.Methods. Newborn rat brainstem-spinal cord preparations were used and superfused with mu-, kappa-, and delta-opioid receptor agonists. Whole cell recordings were performed from three major classes of respiratory neurons (inspiratory, preinspiratory, and expiratory).Results. Mu- and kappa-opioid receptor agonists reduced the spontaneous burst activity of inspiratory neurons and the C4 nerve activity. Forty-two percent of the inspiratory neurons were hyperpolarized and decreased in membrane resistance during opioid-induced respiratory depression. Furthermore, under synaptic block by tetrodotoxin perfusion, similar changes of inspiratory neuronal membrane properties occurred after application of mu- and kappa-opioid receptor agonists. In contrast, resting membrane potential and membrane resistance of preinspiratory and majority of expiratory neurons were unchanged by opioid receptor agonists, even during tetrodotoxin perfusion. Simultaneous recordings of inspiratory and preinspiratory neuronal activities confirmed the selective inhibition of inspiratory neurons caused by mu- and kappa-opioid receptor agonists. Application of opioids reduced the slope of rising of excitatory postsynaptic potentials evoked by contralateral medulla stimulation, resulting in a prolongation of the latency of successive first action potential responses.Conclusions. Mu- and kappa-opioid receptor agonists caused reduction of final motor outputs by mainly inhibiting medullary inspiratory neuron network. This inhibition of inspiratory neurons seems to be a result of both a presynaptic and postsynaptic inhibition. The central respiratory rhythm as reflected by the preinspiratory neuron burst rate was essentially unaltered by the agonists.

Tests were carried out to determine if the tolerance that develops in dorsal-horn network responses of mouse dorsal root ganglion (DRG)-spinal cord explants after chronic exposure to opioids could be accounted for by alterations in the excitability and pharmacologic properties of the afferent DRG ce …

This invention relates to a method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist such as morphine and simultaneously attenuating anti-analgesia, hyperalgesia, hy

Multiple modulatory effects of opioids on the duration of the calcium component of the action potential (APD) of dorsal-root ganglion (DRG) neurons of mouse spinal cord-ganglion explants were studied. The APD of DRG neuron perikarya has been previously shown to be shortened by exposure to high conce …

Low (nanomolar) concentrations of opioid agonists prolong the calcium-dependent component of the action potential duration (APD) of many dorsal root ganglion (DRG) neurons, whereas higher (micromolar) levels shorten the APD. Both effects are blocked by naloxone (1-10 nM). Opioid-induced APD prolonga …

Recordings were made from convergent neurons in trigeminal nucleus caudalis of the rat. These neurons could be activated by both innocuous and noxious mechanical stimuli applied to their excitatory receptive fields on the ipsilateral part of the muzzle. Percutaneous application of suprathreshold, 2 …

The ultra-potent opioid analgesic, etorphine, elicits naloxone-reversible, dose-dependent inhibitory effects, i.e. shortening of the action potential …

At low (< nM) concentrations, mu, delta or kappa opioid peptides as well as morphine and other opioid alkaloids elicit dose-dependent excitatory prolongation of the calcium-dependent component of the action potential duration (APD) of many mouse sensory dorsal root ganglion (DRG) neurons, whereas …

In a previous study we demonstrated that injection (i.p.) of low doses of GM1 ganglioside in mice rapidly attenuates morphine’s analgesic effects. Thi…

In a previous study, we demonstrated that cholera toxin-A subunit, as well as the whole toxin, selectively blocks opioid-induced prolongation of the Ca2+ component of the action potential duration (APD) in dorsal root ganglion (DRG) neurons, indicating mediation of this excitatory effect by Gs-linke …

Recordings were made from convergent neurons in trigeminal nucleus caudalis of the rat. These neurons could be activated by both innocuous and noxious mechanical stimuli applied to their excitatory receptive fields on the ipsilateral part of the muzzle. Percutaneous application of suprathreshold, 2 ms square-wave electrical stimuli to the centre of the excitatory field resulted in responses to A- and C-fibres being observed. The effects on these responses of manual acupuncture performed by a traditional Chinese acupuncturist at the "Zusanli" point on the right hindlimb were compared with the effects induced by acupuncture applied at a non-acupoint, next to "Zusanli". In addition, the effects of acupuncture were compared with the inhibitory effects evoked by noxious thermal stimulation of the left hindlimb on the responses of the same neurons. This last type of inhibition has been described previously by our group and termed diffuse noxious inhibitory controls. Acupuncture, either applied at "Zusanli" or at a non-acupoint and noxious thermal stimulation induced similar strong inhibitory effects on the C-fibre-evoked responses of trigeminal convergent neurons (77.9 +/- 4.4%; 72.5 +/- 4.6% and 78.5 +/- 3.6% inhibition, respectively) and these inhibitions were followed by long-lasting aftereffects. In addition, both the acupuncture- and noxious thermal stimulation-evoked inhibitions were significantly reduced by systemic naloxone (0.4 mg/kg, i.v.). Since the antinociceptive effects elicited by acupuncture (i) had a similar magnitude and time-course to those evoked by noxious thermal stimulation, (ii) exhibited a lack of topographical specificity and (iii) involved an opioidergic link, we would suggest that, at least in our experimental conditions, acupuncture manoeuvres trigger the neuronal mechanisms involved in diffuse noxious inhibitory controls.

Involvement of endogenous opioids in inhibition of luteinizing hormone (LH) release and stimulation of prolactin (PRL) release was investigated by injecting the opioid antagonist naloxone into 18 ewes on d 7 and 8, d 12 and 13, and d 18 and 19 postpartum. Compared with control injections of saline, …

Scientific Reports - Role of opioid receptors in modulation of P2X receptor-mediated cardiac sympathoexcitatory reflex response

Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 °C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 µM concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75% and 90% of repolarization and decreased the short-term variability of APD90. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (Ito) and late sodium current (INa,L) were reduced by approximately 20% and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of Ito. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly INa,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied.

Background: Opioid long-term therapy can produce tolerance, opioid-induced hyperalgesia (OIH), and it induces dysfunction in pain descending pain inhibitory system (DPIS).Objectives: This integrative review with meta-analysis aimed: (i) To discuss the potential mechanisms involved in analgesic tolerance and opioid-induced hyperalgesia (OIH). (ii) To examine how the opioid can affect the function of DPIS. (ii) To show evidence about the tDCS as an approach to treat acute and chronic pain. (iii) To discuss the effect of tDCS on DPIS and how it can counter-regulate the OIH. (iv) To draw perspectives for the future about the tDCS effects as an approach to improve the dysfunction in the DPIS in chronic non-cancer pain.Methods: Relevant published randomized clinical trials (RCT) comparing active (irrespective of the stimulation protocol) to sham tDCS for treating chronic non-cancer pain were identified, and risk of bias was assessed. We searched trials in PubMed, EMBASE and Cochrane trials databases. tDCS protocols accepted were application in areas of the primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), or occipital area.Results: Fifty-nine studies were fully reviewed, and 24 with moderate to the high-quality methodology were included. tDCS improved chronic pain with a moderate effect size [pooled standardized mean difference; −0.66; 95% confidence interval (CI) −0.91 to −0.41]. On average, active protocols led to 27.26% less pain at the end of treatment compa...

Injection of endothelin-1 (ET-1) into the plantar rat hindpaw causes acute pain at high concentrations and tactile sensitization at low concentrations. The pro-nociceptive actions are driven through ET[A] receptors for both levels of [ET-1], but the ...