-
Annual Review of Neuroscience Jul 2018Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and... (Review)
Review
Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.
Topics: Analgesics, Opioid; Animals; Humans; Pain; Pain Perception; Receptors, G-Protein-Coupled
PubMed: 29852083
DOI: 10.1146/annurev-neuro-080317-061522 -
Molecules (Basel, Switzerland) Sep 2020Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for... (Review)
Review
Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.
Topics: Analgesics, Opioid; Arrestin; Furans; Humans; Ligands; Pain; Pyrones; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Signal Transduction
PubMed: 32948048
DOI: 10.3390/molecules25184257 -
Cell Jan 2023Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid...
Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis. The human opioid system contains four opioid receptors (μOR, δOR, κOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs). Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear. Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-G complexes, including β-endorphin- and endomorphin-bound μOR, deltorphin-bound δOR, dynorphin-bound κOR, and nociceptin-bound NOPR. These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation. These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief.
Topics: Humans; Analgesics, Opioid; Opioid Peptides; Receptors, Opioid, mu; Receptors, Opioid
PubMed: 36638794
DOI: 10.1016/j.cell.2022.12.026 -
Pharmacological Reviews Jan 2021Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication,... (Review)
Review
Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development. SIGNIFICANCE STATEMENT: The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.
Topics: Drug Development; Humans; Motivation; Reinforcement, Psychology; Reward; Substance-Related Disorders
PubMed: 33318153
DOI: 10.1124/pharmrev.120.000083 -
Drugs Aug 2018The buprenorphine receptor binding profile is unique in that it binds to all three major opioid receptors (mu, kappa, delta), and also binds to the orphan-like receptor,... (Review)
Review
The buprenorphine receptor binding profile is unique in that it binds to all three major opioid receptors (mu, kappa, delta), and also binds to the orphan-like receptor, the receptor for orphanin FQ/nociceptin, with lower affinity. Within the mu receptor group, buprenorphine analgesia in rodents is dependent on the recently discovered arylepoxamide receptor target in brain, which involves a truncated 6-transmembrane mu receptor gene protein, distinguishing itself from morphine and most other mu opioids. Although originally designed as an analgesic, buprenorphine has mainly been used for opioid maintenance therapy and only now is increasingly recognized as an effective analgesic with an improved therapeutic index relative to certain potent opioids. Albeit a second-, third-, or fourth-line analgesic, buprenorphine is a reasonable choice in certain clinical situations. Transdermal patches and buccal film formulations are now commercially available as analgesics. This review discusses buprenorphine pharmacodynamics and pharmacokinetics, use in certain populations, and provides a synopsis of systematic reviews and randomized analgesic trials. We briefly discuss postoperative management in patients receiving buprenorphine maintenance therapy, opioid equivalence to buprenorphine, rotations to buprenorphine from other opioids, and clinical relevance of buprenorphine-related QTc interval changes.
Topics: Administration, Sublingual; Analgesics, Opioid; Animals; Buprenorphine; Chemistry, Pharmaceutical; Chronic Pain; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug Tolerance; Humans; Narcotic Antagonists; Observational Studies as Topic; Randomized Controlled Trials as Topic; Receptors, Opioid; Substance-Related Disorders; Systematic Reviews as Topic; Transdermal Patch
PubMed: 30051169
DOI: 10.1007/s40265-018-0953-z -
Neuroscience and Biobehavioral Reviews Sep 2022Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating... (Review)
Review
Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.
Topics: Analgesics, Opioid; Animals; Antidepressive Agents; Depression; Humans; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu
PubMed: 35914624
DOI: 10.1016/j.neubiorev.2022.104800 -
Progress in Neuro-psychopharmacology &... Oct 2015There are many processes in which the neuropeptide nociceptin/orphanin FQ (N/OFQ or nociceptin) is involved in the brain. The role of nociceptin in learning and memory... (Review)
Review
There are many processes in which the neuropeptide nociceptin/orphanin FQ (N/OFQ or nociceptin) is involved in the brain. The role of nociceptin in learning and memory holds promise in modulating these processes in health and disease in the human brain. This review summarizes the body of research focused on N/OFQ and its specific receptor, the nociceptin receptor (NOP receptor), in learning and memory, and its potential mechanisms of action, in which acetylcholine, NMDA receptor, and noradrenaline may be critical. Finally, the association between NOP receptor and posttraumatic stress disorder (PTSD), a psychiatric disorder with altered fear learning, is examined as one of the potential outcomes resulting from pathological consequences of dysregulation of N/OFQ-NOP receptor in the brain.
Topics: Animals; Humans; Learning; Memory; Opioid Peptides; Receptors, Opioid; Stress Disorders, Post-Traumatic; Nociceptin Receptor; Nociceptin
PubMed: 25724763
DOI: 10.1016/j.pnpbp.2015.02.007 -
Anesthesiology Sep 2021Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid...
BACKGROUND
Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates.
METHODS
The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses.
RESULTS
Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches).
CONCLUSIONS
In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Female; Fentanyl; Indoles; Injections, Spinal; Macaca mulatta; Male; Opioid Peptides; Pain Measurement; Receptors, Opioid; Receptors, Opioid, mu; Spiro Compounds; Nociceptin Receptor; Nociceptin
PubMed: 34237134
DOI: 10.1097/ALN.0000000000003848 -
Current Opinion in Pharmacology Dec 2015Intestinal inflammation is a major health problem which impairs the quality of life, impacts mental health and is exacerbated by stress and psychiatric disturbances... (Review)
Review
Intestinal inflammation is a major health problem which impairs the quality of life, impacts mental health and is exacerbated by stress and psychiatric disturbances which, in turn, can affect disease prognosis and response to treatment. Accumulating evidence indicates that the immune system is an important interface between intestinal inflammation and the enteric, sensory, central and autonomic nervous systems. In addition, the neuroimmune interactions originating from the gastrointestinal tract are orchestrated by the gut microbiota. This article reviews some major insights into this complex homeostatic network that have been achieved during the past two years and attempts to put these advances into perspective with novel opportunities of pharmacological intervention.
Topics: Animals; Brain; Cannabinoids; Gastrointestinal Tract; Humans; Inflammation; Inflammatory Bowel Diseases; Mast Cells; Opioid Peptides; Vagus Nerve; Nociceptin
PubMed: 26426677
DOI: 10.1016/j.coph.2015.09.003 -
Cells Mar 2022Nociceptin and the nociceptin receptor (NOP) have been described as targets for treatment of pain and inflammation, whereas toll-like receptors (TLRs) play key roles in...
Nociceptin and the nociceptin receptor (NOP) have been described as targets for treatment of pain and inflammation, whereas toll-like receptors (TLRs) play key roles in inflammation and impact opioid receptors and endogenous opioids expression. In this study, interactions between the nociceptin and TLR systems were investigated. Human THP-1 cells were cultured with or without phorbol myristate acetate (PMA 5 ng/mL), agonists specific for TLR2 (lipoteichoic acid, LTA 10 µg/mL), TLR4 (lipopolysaccharide, LPS 100 ng/mL), TLR7 (imiquimod, IMQ 10 µg/mL), TLR9 (oligonucleotide (ODN) 2216 1 µM), PMA+TLR agonists, or nociceptin (0.01−100 nM). Prepronociceptin (ppNOC), NOP, and TLR mRNAs were quantified by RT-qPCR. Proteins were measured using flow cytometry. PMA upregulated ppNOC mRNA, intracellular nociceptin, and cell membrane NOP proteins (all p < 0.05). LTA and LPS prevented PMA’s upregulating effects on ppNOC mRNA and nociceptin protein (both p < 0.05). IMQ and ODN 2216 attenuated PMA’s effects on ppNOC mRNA. PMA, LPS, IMQ, and ODN 2216 increased NOP protein levels (all p < 0.05). PMA+TLR agonists had no effects on NOP compared to PMA controls. Nociceptin dose-dependently suppressed TLR2, TLR4, TLR7, and TLR9 proteins (all p < 0.01). Antagonistic effects observed between the nociceptin and TLR systems suggest that the nociceptin system plays an anti-inflammatory role in monocytes under inflammatory conditions.
Topics: Humans; Inflammation; Lipopolysaccharides; Opioid Peptides; RNA, Messenger; Tetradecanoylphorbol Acetate; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 7; Toll-Like Receptor 9; Toll-Like Receptors; Nociceptin
PubMed: 35406649
DOI: 10.3390/cells11071085