The endocannabinoid system consists of the cannabinoid (CB) receptors, CB[1] and CB[2] , the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis ...

Su, Xin, R. E. Wachtel, and G. F. Gebhart. Inhibition of calcium currents in rat colon sensory neurons by κ- but not μ- or δ-opioids. J. Neurophysiol. 80: 3112–3119, 1998. We previously reported that κ-, but not μ- or δ-opioid receptor agonists (ORAs) have selective, potentially useful peripheral analgesic effects in visceral pain. To evaluate one potential site and mechanism by which these effects are produced, we studied opioid effects on high-voltage activated (HVA) Ca2+ currents in identified (Di-I) pelvic nerve sensory neurons from the S1 dorsal root ganglion (DRG). Results were compared with opioid effects on cutaneous neurons from L5 or L6 DRG. Di-I–labeled DRG cells were voltage clamped (perforated whole cell patch clamp), and HVA Ca2+ currents were evoked by depolarizing 240-ms test pulses to +10 mV from a holding potential of −60 mV. Neither μ-ORAs (morphine, 10−6 M, n = 16; [D-Ala2, N-Me-Phe4, Gly-ol5] enkephalin, 10−6 M, n = 12) nor δ-ORAs ([D-Pen2, D-Pen5] enkephalin, 10−7 M, n = 16; SNC-80, 10−7 M, n = 7) affected HVA Ca2+ currents in colon sensory neurons. In contrast, the κ-ORAs U50,488 (10−6 M), bremazocine (10−6M), and nalBzoH (10−6 M) significantly attenuated HVA Ca2+ currents in colon sensory neurons; effects on cutaneous sensory neurons were variable. A nonreceptor selective concentration of naloxone (10−5 M) and nor-BNI (10−6 M), a selective κ-opioid receptor antagonist, reversed the inhibitory effect of κ-ORAs. In the presence of N-, P-, or Q-, but not L-type Ca2+ channel antagonists, the effect of U50,488 on HVA Ca2+ currents was significantly reduced. Pretreatment with pertussis toxin (PTX) prevented the inhibition by U50,488. These results suggest that κ-opioid receptors are coupled to multiple HVA Ca2+ channels in colon sensory neurons by a PTX-sensitive G protein pathway. We conclude that inhibition of Ca2+ channel function likely contributes in part to the peripheral analgesic action of κ-ORAs in visceral nociception.

The evolution of therapeutics for and management of human immunodeficiency virus-1 (HIV-1) infection has shifted it from predominately manifesting as a severe, acute disease with high mortality to a chronic, controlled infection with a near typical life ...

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 ...

Transient receptor potential vanilloid receptor 1 (TRPV1)-mediated release of neuroactive peptides and neurotransmitters from the peripheral and central terminals of primary sensory neurons can critically contribute to nociceptive processing at the periphery and in the CNS. However, the mechanisms that link TRPV1 activation with Ca2+ signaling at the release sites and neurosecretion are poorly understood. Here we demonstrate that a brief stimulation of the receptor using either capsaicin or the endogenous TRPV1 agonist N -arachidonoyl-dopamine induces a prolonged elevation of presynaptic [Ca2+]i and a concomitant enhancement of glutamate release at sensory synapses. Initiation of this response required Ca2+ entry, primarily via TRPV1. The sustained phase of the response was independent of extracellular Ca2+ and was prevented by inhibitors of mitochondrial Ca2+ uptake and release mechanisms. Measurements using a mitochondria-targeted Ca2+ indicator, mtPericam, revealed that TRPV1 activation elicits a long-lasting Ca2+ elevation in presynaptic mitochondria. The concentration of TRPV1 agonist determined the duration of mitochondrial and cytosolic Ca2+ signals in presynaptic boutons and, consequently, the period of enhanced glutamate release and action potential firing by postsynaptic neurons. These data suggest that mitochondria control vanilloid-induced neurotransmission by translating the strength of presynaptic TRPV1 stimulation into duration of the postsynaptic response.

Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within the United States, the rate of death from opioid abuse since the early 1990s has grown disproportionally, prompting the classification as a nationwide “epidemic.” Since this time, we have begun to unravel many fundamental cellular and systems-level mechanisms associated with opioid-related death. However, factors such as individual vulnerability, neuromodulatory compensation, and redundancy of opioid effects across central and peripheral nervous systems have created a barrier to a concise, integrative view of OIRD. Within this review, we bring together multiple perspectives in the field of OIRD to create an overarching viewpoint of what we know, and where we view this essential topic of research going forward into the future.

Delta (δ) opioid receptors (DORs) are part of circuits involved in many physiological functions including the modulation of pain. Activation of DORs appears to mediate antinociception and antihyperalgesia in many conditions including stress, chronic pain,...

Capsaicin, the pungent ingredient in hot pepper, activates nociceptors to produce pain and inflammation. However, repeated exposures of capsaicin will cause desensitization to nociceptive stimuli. In cultured trigeminal ganglion (TG) neurons, we investigated mechanisms underlying capsaicin-mediated inhibition of action potentials (APs) and modulation of voltage-gated sodium channels (VGSCs). Capsaicin (1 μM) inhibited APs and VGSCs only in capsaicin-sensitive neurons. Repeated applications of capsaicin produced depolarizing potentials but failed to evoke APs. The capsaicin-induced inhibition of VGSCs was prevented by preexposing the capsaicin receptor antagonist, capsazepine (CPZ). The magnitude of the capsaicin-induced inhibition of VGSCs was dose dependent, having aK 1/2 = 0.45 μM. The magnitude of the inhibition of VGSCs was proportional to the capsaicin induced current (for –I CAP < 0.2 nA). Capsaicin inhibited activation of VGSCs without changing the voltage dependence of activation or markedly changing channel inactivation and use-dependent block. To explore the changes leading to this inhibition, it was found that capsaicin increased cAMP with aK 1/2 = 0.18 μM. At 1 μM capsaicin, this cAMP generation was inhibited 64% by10 μM CPZ, suggesting that activation of capsaicin receptors increased cAMP. The addition of 100 μM CPT-cAMP increased the capsaicin-activated currents but inhibited the VGSCs in both capsaicin-sensitive and -insensitive neurons. In summary, the inhibitory effects of capsaicin on VGSCs and the generation of APs are mediated by activation of capsaicin receptors. The capsaicin-induced activation of second messengers, such as cAMP, play a part in this modulation. These data distinguish two pathways by which neuronal sensitivity can be diminished by capsaicin: by modulation of the capsaicin receptor sensitivity, since the block of VGSCs is proportional to the magnitude of the capsaicin-evoked currents, and by modulation of VGSCs through second messengers elevated by capsaicin receptor activation. These mechanisms are likely to be important in understanding the analgesic effects of capsaicin.

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This ...

The present invention provides a method for increasing analgesic potency of a bimodally-acting opioid agonist in a subject, by inhibiting GM1-ganglioside in nociceptive neurons. The present invention

Modulatory effects of Gs-coupled excitatory opioid receptor functions on opioid analgesia, tolerance, and dependence | Stanley M. Crain; Ke-Fei Shen | download | BookSC. Download books for free. Find books

Cough: Causes, Mechanisms and Therapy Edited byKian Fan Chung MD DSc FRCPNational Heart and Lung Institute Imperial ...

/)JCHURCHIU 1IVINGSTONlAn Imprint of Elsevier Science 11830 Westline Industrial Drive St. Louis, Missouri 63146PHY...

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Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1–4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain. Their role in heart rate, neuronal pacemaking, dendritic integration, learning and memory, and visual and pain perceptions has been extensively studied; these channels have been found also in some peripheral tissues, where their functions still need to be fully elucidated. Genetic defects and altered expression of HCN channels are linked to several pathologies, which makes these proteins attractive targets for translational research; at the moment only one drug (ivabradine), which specifically blocks the hyperpolarization-activated current, is clinically available. This review discusses current knowledge about HCN channels, starting from their biophysical properties, origin, and developmental features, to (patho)physiologic role in different tissues and pharmacological modulation, ending with their present and future relevance as drug targets.

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Neuropsychopharmacology - ACNP 56th Annual Meeting: Panels, Mini-Panels and Study Groups, December 4 – 7, 2017

U.S. Patent Number RE036547 for Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists

Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca(2+)-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening. The present study provides a cellular mechanism to account for previous reports that low doses of NLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists. Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists. These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability. Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development of withdrawal symptoms in chronic, as well as acute, physical dependence assays.

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The mechanism of action of the dimeric enkephalin peptide, biphalin (Tyr-D-Ala-Gly-Phe-NH2)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 du …