scholarly journals Cebranopadol: A first-in-class nociceptin receptor agonist for managing chronic pain

2020 ◽  
Vol 26 (1) ◽  
pp. 147
Author(s):  
AbhijitS Nair ◽  
ShyamPrasad Mantha ◽  
SaiKaushik Pulipaka ◽  
BasanthKumar Rayani
Keyword(s):  
Chronic Pain ◽  
Receptor Agonist ◽  
Nociceptin Receptor

scholarly journals Buprenorphine C7‐Esters with Improved Nociceptin Receptor Agonist Potency as Analgesics

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Keith Mathew Olson ◽  
Gerta Cami‐Kobeci ◽  
Stephen M. Husbands ◽  
John R. Traynor
Keyword(s):  
Receptor Agonist ◽  
Nociceptin Receptor

scholarly journals Antinociception induced by a novel α2A adrenergic receptor agonist in rodents acute and chronic pain models

2017 ◽  
Vol 815 ◽  
pp. 210-218 ◽  
Author(s):  
Roberto Takashi Sudo ◽  
Rachel Vieiralves do Amaral ◽  
Carlos Eduardo da Silva Monteiro ◽  
Ivan da Rocha Pitta ◽  
Maria do Carmo Lima ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Adrenergic Receptor ◽  
Receptor Agonist ◽  
Pain Models ◽  
Adrenergic Receptor Agonist

Targeting Nociceptin Receptor to Treat Pain in Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 373-373
Author(s):  
Derek Vang ◽  
Lucile Vincent ◽  
Katherine NH Johnson ◽  
Nurulaim Zaveri ◽  
Kalpna Gupta
Keyword(s):  
Chronic Pain ◽  
Blood Flow ◽  
Sickle Cell Disease ◽  
Skin Temperature ◽  
Thermal Sensitivity ◽  
Cell Disease ◽  
Mechanical Sensitivity ◽  
Deep Tissue ◽  
And Control ◽  
Nociceptin Receptor

Abstract Abstract 373 Morphine and its congeners remain a sub-optimal approach to treat pain in sickle cell disease (SCD) due to side effects, risk of addiction, and development of tolerance. To avoid these liabilities associated with use of morphine and mu opioid receptor (MOR) agonist analgesics, we examined the ability of nociceptin receptor (NOPR) ligands to treat pain in SCD. The NOPR and its endogenous ligand nociceptin/orphanin FQ (N/OFQ) belonging to the opioid receptor (OR) and opioid family respectively, are involved in nociceptive signaling. Small molecule NOPR agonists are non-addicting, while providing analgesia in acute and chronic pain models. We used AT-200 ([1-(1-cyclooctylpiperidin-4-yl)-indolin-2-one), which has high binding affinity and agonist efficacy at NOPR and low efficacy, partial agonist activity at MOR, to treat chronic and hypoxia/reoxygenation (H/R)-evoked pain, in sickle HbSS-BERK and control HbAA-BERK mice, expressing sickle and normal human hemoglobin, respectively. AT-200 was injected subcutaneously at a dose of 10 mg/Kg. Equal number of mice were treated with vehicle in parallel. Pain behaviors were analyzed over a period of time in the following paradigms [i] under normoxia after a single dose of AT-200, [ii] after injecting AT-200 following the incitement of H/R, and [iii] AT-200 given everyday for 7 days. For comparison, we used 20 mg/Kg morphine treatment following H/R. Pain measures that were characterized included deep tissue pain by grip force measurement, cutaneous hyperalgesia by mechanical sensitivity to von Frey filaments and thermal sensitivity to heat and cold as described by us for sickle mice (Kohli et al., Blood 2010). Blood flow and dorsal skin temperature were measured using laser doppler velocimetry and infrared thermography, respectively. The measure of mechanical threshold and suprathreshold to a 1.0 g von Frey fiber showed a significant reduction in mechanical sensitivity even 24h after AT-200 treatment as compared to vehicle under normoxia (p<0.05 for threshold and p<0.005 for suprathreshold) in sickle mice. H/R evoked a persistent increase in mechanical hyperalgesia in sickle mice up to 24h and in control mice up to 4h, and both were ameliorated by AT-200. Morphine reduced mechanical hyperalgesia following H/R in sickle mice up to 4h but not 24h and its effect was significantly less than that of AT-200. H/R-incitement increased deep pain for 24h in sickle mice and for 30 min in control mice and AT-200 ameliorated both. Interestingly, morphine significantly blocked deep pain at 30 min following H/R (p<0.005), but remained ineffective thereafter in sickle mice. Since deep pain appears is a characteristic feature of vasoocclusive pain in sickle mice as compared to cutaneous pain, it is likely that AT-200 acts as a superior analgesic with a long-lasting effect to treat sickle-specific vasoocclusive pain, compared to morphine. Heat and cold sensitivity were persistently elevated in sickle mice up to 24h post-H/R but returned to baseline (before H/R) in control mice. Both, AT-200 and morphine inhibited the H/R-induced thermal sensitivity up to 24h, in sickle mice, but the effect of AT-200 was significantly more remarkable than morphine. Blood flow and skin temperature increased significantly following H/R in sickle mice (p<0.05 for both vs baseline before H/R) and were significantly reduced by AT-200 and morphine equally, suggesting that both drugs have a similar acute effect on vascular physiology and inflammation in sickle mice. The enhanced analgesic effectiveness of AT-200 compared to morphine, in sickle mice could be due to a ∼2-fold increase in NOPR expression in the dorsal root ganglion of sickle mice compared to control, observed by qPCR in this study. Chronic pain conditions, including pain in sickle mice, are characterized by reduced MOR expression peripherally and in the spinal cord. However, spinal NOPR expression by qPCR did not show a significant difference between sickle and control mice. AT-200 was effective in treating chronic cutaneous, deep tissue and thermal hyperalgesia even after 7 days of continuous treatment without causing tolerance. Thus, AT-200 provided an analgesic effect in chronic pain and that evoked by H/R, without the development of analgesic tolerance in sickle mice. Targeting NOPR appears to be a promising strategy warranting further development of novel NOPR agonists to treat pain in SCD. Disclosures: No relevant conflicts of interest to declare.

The kappa opioid receptor agonist SA14867 has antinociceptive and weak sedative effects in models of acute and chronic pain

2011 ◽  
Vol 671 (1-3) ◽  
pp. 53-60 ◽  
Author(s):  
Yaeko Tsukahara-Ohsumi ◽  
Fumio Tsuji ◽  
Masashi Niwa ◽  
Taeko Hata ◽  
Minoru Narita ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Opioid Receptor Agonist ◽  
Sedative Effects

scholarly journals Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice

Haematologica ◽  
2015 ◽  
Vol 100 (12) ◽  
pp. 1517-1525 ◽  
Author(s):  
D. Vang ◽  
J. A. Paul ◽  
J. Nguyen ◽  
H. Tran ◽  
L. Vincent ◽  
...  
Keyword(s):  
Mast Cell ◽  
Small Molecule ◽  
Receptor Agonist ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Nociceptin Receptor

scholarly journals Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

2020 ◽  
Author(s):  
Nathan Cramer ◽  
Gleice Kelli Silva-Cardoso ◽  
Asaf Keller
Keyword(s):  
Chronic Pain ◽  
Synaptic Transmission ◽  
Signaling Pathways ◽  
Receptor Agonist ◽  
Pain Perception ◽  
Neuronal Excitability ◽  
Opioid Peptide ◽  
Synaptic Activity ◽  
Parabrachial Nucleus ◽  
List Type

AbstractThe parabrachial nucleus (PB) is a hub for aversive behaviors, including those related to pain. We have shown that the expression of chronic pain is causally related to amplified activity of PB neurons, and to changes in synaptic inhibition of these neurons. These findings indicate that regulation of synaptic activity in PB may modulate pain perception and be involved in the pathophysiology of chronic pain. Here, we identify the roles in PB of signaling pathways that modulate synaptic functions. In pharmacologically isolated lateral PB neurons in acute mouse slices, we find that baclofen, a GABAB receptor agonist, suppresses the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSC). Activation of µ-opioid peptide receptors with DAMGO had similar effects, while the k-opioid peptide receptor agonist U-69593 suppressed mIPSC release but had no consistent effects on mEPSCs. Activation of cannabinoid type 1 receptors with WIN 55,212-2 reduced the frequency of both inhibitory and excitatory synaptic events, while the CB1 antagonist AM251 had opposite effects on mIPSC and mEPSC frequencies. AM251 increased the frequency of inhibitory events but led to a reduction in excitatory events through a GABAB mediated mechanism. Although none of the treatments produced a consistent effect on mIPSC or mEPSC amplitudes, baclofen and DAMGO both reliably activated a postsynaptic conductance. Together, these results demonstrate that signaling pathways known to modulate nociception, alter synaptic transmission and neuronal excitability in the lateral parabrachial nucleus and provide a basis for investigating the contributions of these systems to the development and maintenance of chronic pain.HighlightsThe parabrachial nucleus (PB) is a hub for processing interoceptive and exteroceptive noxious stimuli, including pain.Synaptic activity in PB is abnormal in chronic pain.Synaptic activity in PB is regulated by presynaptic and postsynaptic GABAB, opioid µ and k, and cannabinoid CB1 receptors.GABAergic presynaptic terminals are most potently regulated by these receptors.Changes in the strength of these modulatory pathways may contribute to increased PB excitability and, consequently, chronic pain.

scholarly journals Is Kratom the New ‘Legal High’ on the Block?: The Case of an Emerging Opioid Receptor Agonist with Substance Abuse Potential

2017 ◽  
Vol 1 (21;1) ◽  
pp. E195-E198 ◽  
Author(s):  
George C. Chan ge Chien
Keyword(s):  
Substance Abuse ◽  
Chronic Pain ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Abuse Potential ◽  
Herbal Extract ◽  
Opioid Overdose ◽  
Opioid Receptor Agonist ◽  
Chronic Pain Patients ◽  
Pain Patients

Kratom is an unscheduled herbal extract that contains alkaloids with opioid receptor agonist activity. It is currently available in the form of dietary supplements and is used and abused by chronic pain patients on prescription opioids. Active alkaloids isolated from Kratom such as mitragynine and 7-hydroxymitragynine are thought to act on mu and delta opioid receptors as well as alpha 2 adrenergic and 5-HT2A receptors. Animal studies suggest that Kratom may be more potent than morphine. Consequently, Kratom consumption produces analgesic and euphoric feelings among users. Some chronic pain patients on opioids take Kratom to counteract the effects of opioid withdrawal. Although the Food and Drug Administration has banned its use as a dietary supplement, Kratom continues to be widely available and easily accessible on the internet at much lower prices than other opioid replacement therapies like buprenorphine. There are no Federal regulations monitoring the sale and distribution of this substance. Consumption of Kratom has been associated with hallucination, delusion, depression, myalgia, chill, nausea/vomiting, respiratory depression, hepatotoxicity, seizure, coma and death. A search of the pain literature shows past research has not described the use and potential deleterious effects of this extract. Many pain physicians are not familiar with Kratom. As providers who take care of high-risk chronic pain patients using prescribed opioids, knowledge of all current substances with opioid receptor agonists with abuse potential is of paramount importance. The goal of this article is to introduce Kratom to pain specialists and identify issues for further studies that will be required to help better understand the clinical and long-term effects of Kratom use among chronic pain patients. Key words: Opioid receptor agonist, Kratom, Mitragynine, opioid overdose, chronic pain, substance abuse :

scholarly journals Understanding Buprenorphine for Use in Chronic Pain: Expert Opinion

Pain Medicine ◽  
2020 ◽  
Vol 21 (4) ◽  
pp. 714-723 ◽  
Author(s):  
Lynn Webster ◽  
Jeffrey Gudin ◽  
Robert B Raffa ◽  
Jay Kuchera ◽  
Richard Rauck ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Pain Management ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Relevant Literature ◽  
Analgesic Efficacy ◽  
Chronic Pain Management ◽  
Opioid Dose ◽  
Opioid Receptor Agonist ◽  
Clinical Scenarios

Abstract Objective An expert panel convened to reach a consensus on common misconceptions surrounding buprenorphine, a Schedule III partial µ-opioid receptor agonist indicated for chronic pain. The panel also provided clinical recommendations on the appropriate use of buprenorphine and conversion strategies for switching to buprenorphine from a full µ-opioid receptor agonist for chronic pain management. Methods The consensus panel met on March 25, 2019, to discuss relevant literature and provide recommendations on interpreting buprenorphine as a partial µ-opioid receptor agonist, prescribing buprenorphine before some Schedule II, III, or IV options, perioperative/trauma management of patients taking buprenorphine, and converting patients from a full µ-opioid receptor agonist to buprenorphine. Results The panel recommended that buprenorphine’s classification as a partial µ-opioid receptor agonist not be clinically translated to mean partial analgesic efficacy. The panel also recommended that buprenorphine be considered before some Schedule II, III, or IV opioids in patients with a favorable risk/benefit profile on the basis of metabolic factors, abuse potential, and tolerability and that buprenorphine be continued during the perioperative/trauma period. In addition, switching patients from a full µ-opioid receptor agonist to buprenorphine should be considered with no weaning period at starting doses that are based on the previous opioid dose. Conclusions These recommendations provide a framework for clinicians to address most clinical scenarios regarding buprenorphine use. The overall consensus of the panel was that buprenorphine is a unique Schedule III opioid with favorable pharmacologic properties and a safety profile that may be desirable for chronic pain management.

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