scholarly journals Receptor and Molecular Targets for the Development of Novel Opioid and Non-Opioid Analgesic Therapies

2021 ◽  
pp. 153-163
Keyword(s):  
Chronic Pain ◽  
Key Words ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Opioid Analgesic ◽  
Opioid Analgesics ◽  
Transient Receptor Potential Vanilloid ◽  
Nociceptive Transmission ◽  
Pubmed Database

BACKGROUND: Although conventional pain relief therapeutics have centered around μ-opioid agonists, these drugs are limited by adverse side effects, including respiratory depression and addiction potential. The ongoing opioid epidemic has galvanized research into novel analgesic therapies with more favorable profiles. New pharmacologic agents have been developed to target neuronal pathways involved in pain sensation. Certain receptors have been recognized to mediate nociceptive transmission, central sensitization, and the development of chronic pain states. OBJECTIVES: We conducted a literature review to identify potential targets for novel analgesic therapies. STUDY DESIGN: This study is a narrative review of potential analgesic targets. We characterize their antinociceptive mechanisms of action and evaluate their therapeutic potential. METHODS: A systemized search of available literature on novel analgesics was performed. A search was performed through the PubMed database to identify articles with key words of “novel analgesics,” “novel non-opioid analgesics,” “novel pain targets,” and “non-opioid analgesics.” Potential drug classes were identified and researched through corresponding keywords, with an emphasis on publications from 2018 to 2020. Older articles were included if frequently referenced by current literature. RESULTS: Potential novel analgesic targets include Nav1.7, Nav1.8, CaV2.2, and transient receptor potential vanilloid-1 (TRPV1) cation channel receptors in the peripheral nervous system. Other approaches disrupt the synthesis of pronociceptive signaling molecules such as nitric oxide, prostaglandin E2, and interleukin-6 (IL-6). Within central pain pathways, modification of -opioid, -opioid, N-methyl-D-aspartate, and cannabinoid receptors have been investigated in chronic pain and hyperalgesia models. Recent advances in molecular technology have also presented opportunities to modify protein expression or the cellular genome altogether. LIMITATIONS: Several analgesic targets have only demonstrated efficacy in preclinical trials. There are limited data evaluating the long-term safety profiles of therapies further on in development. CONCLUSIONS: We provide an overview of potential analgesic therapies in various stages of development, which may become clinically relevant in the near future. Some drugs such as TRPV1 agonists, anti-IL-6, and anti-nerve growth factor antibodies have demonstrated analgesic effect in specific clinical pain states. KEY WORDS: Nav1.7, Cav2.2, TRPV1, mPGES-1, IL-6, FAAH, NGF, gene therapy

scholarly journals Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research

2021 ◽  
Vol 22 (4) ◽  
pp. 1863
Author(s):  
Philippe A. Melas ◽  
Maria Scherma ◽  
Walter Fratta ◽  
Carlo Cifani ◽  
Paola Fadda
Keyword(s):  
Mood Disorders ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Molecular Targets ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Preclinical Research ◽  
Neuropsychiatric Diseases ◽  
Transient Receptor

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes.

scholarly journals Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoid/endovanilloid system

2012 ◽  
Vol 367 (1607) ◽  
pp. 3286-3299 ◽  
Author(s):  
Katarzyna Starowicz ◽  
Barbara Przewlocka
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Pain Treatment ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Glutamate Antagonists ◽  
Trpv1 Channels ◽  
Pharmacological Targets

Neuropathic pain refers to chronic pain that results from injury to the nervous system. The mechanisms involved in neuropathic pain are complex and involve both peripheral and central phenomena. Although numerous pharmacological agents are available for the treatment of neuropathic pain, definitive drug therapy has remained elusive. Recent drug discovery efforts have identified an original neurobiological approach to the pathophysiology of neuropathic pain. The development of innovative pharmacological strategies has led to the identification of new promising pharmacological targets, including glutamate antagonists, microglia inhibitors and, interestingly, endogenous ligands of cannabinoids and the transient receptor potential vanilloid type 1 (TRPV1). Endocannabinoids (ECs), endovanilloids and the enzymes that regulate their metabolism represent promising pharmacological targets for the development of a successful pain treatment. This review is an update of the relationship between cannabinoid receptors (CB1) and TRPV1 channels and their possible implications for neuropathic pain. The data are focused on endogenous spinal mechanisms of pain control by anandamide, and the current and emerging pharmacotherapeutic approaches that benefit from the pharmacological modulation of spinal EC and/or endovanilloid systems under chronic pain conditions will be discussed.

scholarly journals Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action

2020 ◽  
Vol 11 ◽  
Author(s):  
Nobuko Ohashi ◽  
Tatsuro Kohno
Keyword(s):  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Nociceptive Transmission ◽  
Spinal Dorsal ◽  
C Fibers ◽  
Trpv1 Receptors ◽  
The Brain

Acetaminophen is one of the most commonly used analgesic agents for treating acute and chronic pain. However, its metabolism is complex, and its analgesic mechanisms have not been completely understood. Previously, it was believed that acetaminophen induces analgesia by inhibiting cyclooxygenase enzymes; however, it has been considered recently that the main analgesic mechanism of acetaminophen is its metabolization to N-acylphenolamine (AM404), which then acts on the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid 1 receptors in the brain. We also recently revealed that the acetaminophen metabolite AM404 directly induces analgesia via TRPV1 receptors on terminals of C-fibers in the spinal dorsal horn. It is known that, similar to the brain, the spinal dorsal horn is critical to pain pathways and modulates nociceptive transmission. Therefore, acetaminophen induces analgesia by acting not only on the brain but also the spinal cord. In addition, acetaminophen is not considered to possess any anti-inflammatory activity because of its weak inhibition of cyclooxygenase (COX). However, we also revealed that AM404 induces analgesia via TRPV1 receptors on the spinal dorsal horn in an inflammatory pain rat model, and these analgesic effects were stronger in the model than in naïve rats. The purpose of this review was to summarize the previous and new issues related to the analgesic mechanisms of acetaminophen. We believe that it will allow clinicians to consider new pain management techniques involving acetaminophen.

scholarly journals Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation

2022 ◽  
Vol 15 ◽  
Author(s):  
Nynke J. van den Hoogen ◽  
Erika K. Harding ◽  
Chloé E. D. Davidson ◽  
Tuan Trang
Keyword(s):  
Chronic Pain ◽  
Immune Cells ◽  
Therapeutic Potential ◽  
Emotional Experience ◽  
Opioid Analgesics ◽  
Pain Modulation ◽  
Pain Outcomes ◽  
Cb2 Receptors ◽  
Affective Components ◽  
Peripheral Immune Cells

Chronic pain is a complex sensory, cognitive, and emotional experience that imposes a great personal, psychological, and socioeconomic burden on patients. An estimated 1.5 billion people worldwide are afflicted with chronic pain, which is often difficult to treat and may be resistant to the potent pain-relieving effects of opioid analgesics. Attention has therefore focused on advancing new pain therapies directed at the cannabinoid system because of its key role in pain modulation. Endocannabinoids and exogenous cannabinoids exert their actions primarily through Gi/o-protein coupled cannabinoid CB1 and CB2 receptors expressed throughout the nervous system. CB1 receptors are found at key nodes along the pain pathway and their activity gates both the sensory and affective components of pain. CB2 receptors are typically expressed at low levels on microglia, astrocytes, and peripheral immune cells. In chronic pain states, there is a marked increase in CB2 expression which modulates the activity of these central and peripheral immune cells with important consequences for the surrounding pain circuitry. Growing evidence indicate that interventions targeting CB1 or CB2 receptors improve pain outcomes in a variety of preclinical pain models. In this mini-review, we will highlight recent advances in understanding how cannabinoids modulate microglia function and its implications for cannabinoid-mediated analgesia, focusing on microglia-neuron interactions within the spinal nociceptive circuitry.

scholarly journals The Vertical and Horizontal Pathways in the Monkey Retina Are Modulated by Typical and Atypical Cannabinoid Receptors

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3160
Author(s):  
Joseph Bouskila ◽  
Maxime Bleau ◽  
Catarina Micaelo-Fernandes ◽  
Jean-François Bouchard ◽  
Maurice Ptito
Keyword(s):  
G Protein ◽  
Visual Information ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Expression Patterns ◽  
Retinal Function ◽  
Age Related Macular Degeneration ◽  
Transient Receptor Potential Vanilloid ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

The endocannabinoid (eCB) system has been found in all visual parts of the central ner-vous system and plays a role in the processing of visual information in many species, including monkeys and humans. Using anatomical methods, cannabinoid receptors are present in the monkey retina, particularly in the vertical glutamatergic pathway, and also in the horizontal GABAergic pathway. Modulating the eCB system regulates normal retinal function as demonstrated by electrophysiological recordings. The characterization of the expression patterns of all types of cannabinoid receptors in the retina is progressing, and further research is needed to elucidate their exact role in processing visual information. Typical cannabinoid receptors include G-protein coupled receptor CB1R and CB2R, and atypical cannabinoid receptors include the G-protein coupled receptor 55 (GPR55) and the ion channel transient receptor potential vanilloid 1 (TRPV1). This review focuses on the expression and localization studies carried out in monkeys, but some data on other animal species and humans will also be reported. Furthermore, the role of the endogenous cannabinoid receptors in retinal function will also be presented using intraocular injections of known modulators (agonists and antagonists) on electroretinographic patterns in monkeys. The effects of the natural bioactive lipid lysophosphatidylglucoside and synthetic FAAH inhibitor URB597 on retinal function, will also be described. Finally, the potential of typical and atypical cannabinoid receptor acti-vity regulation in retinal diseases, such as age-related macular degeneration, diabetic retinopathy, glaucoma, and retinitis pigmentosa will be briefly explored.

scholarly journals Modulation of Endocannabinoid-Binding Receptors in Human Neuroblastoma Cells by Tunicamycin

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1432 ◽  
Author(s):  
Cinzia Rapino ◽  
Annalisa Castellucci ◽  
Anna Rita Lizzi ◽  
Annalaura Sabatucci ◽  
Clotilde B. Angelucci ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Specific Inhibitor ◽  
Transient Receptor Potential Vanilloid ◽  
Post Translational Modification ◽  
Membrane Expression ◽  
Human Neuroblastoma ◽  
Morphological Studies ◽  
Gene And Protein Expression

Endocannabinoid (eCB)-binding receptors can be modulated by several ligands and membrane environment, yet the effect of glycosylation remains to be assessed. In this study, we used human neuroblastoma SH-SY5Y cells to interrogate whether expression, cellular localization, and activity of eCB-binding receptors may depend on N-linked glycosylation. Following treatment with tunicamycin (a specific inhibitor of N-linked glycosylation) at the non-cytotoxic dose of 1 µg/mL, mRNA, protein levels and localization of eCB-binding receptors, as well as N-acetylglucosamine (GlcNAc) residues, were evaluated in SH-SY5Y cells by means of quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), fluorescence-activated cell sorting (FACS), and confocal microscopy, respectively. In addition, the activity of type-1 and type-2 cannabinoid receptors (CB1 and CB2) was assessed by means of rapid binding assays. Significant changes in gene and protein expression were found upon tunicamycin treatment for CB1 and CB2, as well as for GPR55 receptors, but not for transient receptor potential vanilloid 1 (TRPV1). Deglycosylation experiments with N-glycosidase-F and immunoblot of cell membranes derived from SH-SY5Y cells confirmed the presence of one glycosylated form in CB1 (70 kDa), that was reduced by tunicamycin. Morphological studies demonstrated the co-localization of CB1 with GlcNAc residues, and showed that tunicamycin reduced CB1 membrane expression with a marked nuclear localization, as confirmed by immunoblotting. Cleavage of the carbohydrate side chain did not modify CB receptor binding affinity. Overall, these results support N-linked glycosylation as an unprecedented post-translational modification that may modulate eCB-binding receptors’ expression and localization, in particular for CB1.

Internet Based Drug Design of New Opioid Analgesics

2018 ◽  
Vol 5 (3) ◽  
Author(s):  
Avnish Kaur ◽  
Meenakshi Mehra ◽  
Mumtaz Ahmed
Keyword(s):  
Drug Design ◽  
Therapeutic Potential ◽  
Opioid Analgesic ◽  
Opioid Analgesics ◽  
Rational Drug Design ◽  
Input Structure ◽  
Rational Drug ◽  
Structural Activity Relationship ◽  
Sar Study ◽  
Use Of Internet

The development of new drug with its therapeutic potential is one of the most vital process in pharmaceutical industry. Now a day, there is development and importance of computational chemistry including molecular docking and a SAR study which deals with pharmacophore based drug design approach. Also, the methodology linked with modification of the target based drug discovery has been performed by using various computational tools. Thus, the present study deals with the Structural Activity Relationship study and pharmacophore based drug design approaches with the use of internet based tools which are free of cost and compatible with any platform. Here, attempts are made to design OPIORPHIN analogue by pharmacophore study to design more potent or equivalent opioid analgesic using free internet based tools by using Java platform to input structure, calculate its drug likeness, molecular properties and toxicity which are important parameters for structure based rational drug design.

scholarly journals Structure–Activity Relationship Analysis of Benzimidazoles as Emerging Anti-Inflammatory Agents: An Overview

2021 ◽  
Vol 14 (7) ◽  
pp. 663
Author(s):  
Ravichandran Veerasamy ◽  
Anitha Roy ◽  
Rohini Karunakaran ◽  
Harish Rajak
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Structure Activity Relationship ◽  
Inflammatory Activity ◽  
Activity Relationship ◽  
Transient Receptor Potential Vanilloid ◽  
Relationship Analysis ◽  
Structure Activity ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

A significant number of the anti-inflammatory drugs currently in use are becoming obsolete. These are exceptionally hazardous for long-term use because of their possible unfavourable impacts. Subsequently, in the ebb-and-flow decade, analysts and researchers are engaged in developing new anti-inflammatory drugs, and many such agents are in the later phases of clinical trials. Molecules with heterocyclic nuclei are similar to various natural antecedents, thus acquiring immense consideration from scientific experts and researchers. The arguably most adaptable heterocyclic cores are benzimidazoles containing nitrogen in a bicyclic scaffold. Numerous benzimidazole drugs are broadly used in the treatment of numerous diseases, showing promising therapeutic potential. Benzimidazole derivatives exert anti-inflammatory effects mainly by interacting with transient receptor potential vanilloid-1, cannabinoid receptors, bradykinin receptors, specific cytokines, 5-lipoxygenase activating protein and cyclooxygenase. Literature on structure–activity relationship (SAR) and investigations of benzimidazoles highlight that the substituent’s tendency and position on the benzimidazole ring significantly contribute to the anti-inflammatory activity. Reported SAR analyses indicate that substitution at the N1, C2, C5 and C6 positions of the benzimidazole scaffold greatly influence the anti-inflammatory activity. For example, benzimidazole substituted with anacardic acid on C2 inhibits COX-2, and 5-carboxamide or sulfamoyl or sulfonyl benzimidazole antagonises the cannabinoid receptor, whereas the C2 diarylamine and C3 carboxamide substitution of the benzimidazole scaffold result in antagonism of the bradykinin receptor. In this review, we examine the insights regarding the SARs of anti-inflammatory benzimidazole compounds, which will be helpful for researchers in designing and developing potential anti-inflammatory drugs to target inflammation-promoting enzymes.

scholarly journals Augmented Chondroitin Sulfate Proteoglycan Has Therapeutic Potential for Intervertebral Disc Degeneration by Stimulating Anabolic Turnover in Bovine Nucleus Pulposus Cells under Changes in Hydrostatic Pressure

2021 ◽  
Vol 22 (11) ◽  
pp. 6015
Author(s):  
Yoshiki Takeoka ◽  
Phani Paladugu ◽  
James D. Kang ◽  
Shuichi Mizuno
Keyword(s):  
Hydrostatic Pressure ◽  
Intervertebral Disc ◽  
Chondroitin Sulfate ◽  
Nucleus Pulposus ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Chondroitin Sulfate Proteoglycan ◽  
Transient Receptor Potential Vanilloid ◽  
Type I ◽  
Sulfate Proteoglycan

Nucleus pulposus (NP) cells are exposed to changes in hydrostatic pressure (HP) and osmotic pressure within the intervertebral disc. We focused on main disc matrix components, chondroitin sulfate proteoglycan (CSPG) and hyaluronan (HA) to elucidate the capability of augmented CSPG to enhance the anabolism of bovine NP (bNP) cells under repetitive changes in HP at high osmolality. Aggrecan expression with CSPG in the absence of HP was significantly upregulated compared to the no-material control (phosphate buffer saline) under no HP at 3 days, and aggrecan expression with CSPG under HP was significantly higher than the control with HA under HP at 12 days. Collagen type I expression under no HP was significantly lower with CSPG than in controls at 3 days. Although matrix metalloproteinase 13 expression under HP was downregulated compared to no HP, it was significantly greater with HA than the control and CSPG, even under HP. Immunohistology revealed the involvement of mechanoreceptor of transient receptor potential vanilloid-4 activation under HP, suggesting an HP transduction mechanism. Addition of CSPG had anabolic and anti-fibrotic effects on bNP cells during the early culture period under no HP; furthermore, it showed synergy with dynamic HP to increase bNP-cell anabolism at later time points.

Sign in / Sign up

Export Citation Format

Share Document