Development Of Analgesic Drugs Research Articles

Synthesis and evaluation of a novel analgesic conotoxin Lt7b that inhibits calcium currents and increases sodium currents

Conotoxins are promising neuropharmacological tools and drug candidates due to their high efficiency and specificity in targeting ion channels or neurotransmitter receptors. In this study, a novel O2‐superfamily conotoxin, Lt7b, was synthesized and its pharmacological functions were evaluated. Lt7b with three modified amino acids and three disulfide bonds was successfully synthesized. CD spectra showed that Lt7b had a typical α‐helix in the secondary structure. Patch clamp experiments on rat DRG neurons showed that Lt7b could significantly inhibit calcium currents with an IC50 value of 856 ± 95 nM. Meanwhile, 10 μM Lt7b could significantly increase the sodium currents by 77 ± 8%, but it had no obvious effects on the potassium currents in DRG neurons. In addition, patch clamp experiments on ion channel subtypes showed that 10 μM Lt7b could inhibit 7.0 ± 1.2%, 8.0 ± 1.5%, 4.6 ± 3.4%, and 9.5 ± 0.1% of the hCav1.2, hCav2.1, hCav2.2, and hCav3.2 currents, respectively, while it did not increase the rNav1.7, rNav1.8, hNav1.5, hNav1.7, and hNav1.8 currents. Lt7b had no obvious toxicity to HaCaT and ND7/23 cells up to 1 mM and significantly increased the pain threshold at the testing time of 0.5–4 h in a dose‐dependent manner in the mouse hotplate assay. This novel conotoxin Lt7b may be a useful tool for ion channel studies and analgesic drug development.

Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development.

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development.

The transient receptor potential vanilloid 1 (TRPV1) ion channel plays an important role in the peripheral nociceptive pathway. TRPV1 is a polymodal receptor that can be activated by multiple types of ligands and painful stimuli, such as noxious heat and protons, and contributes to various acute and chronic pain conditions. Therefore, TRPV1 is emerging as a novel therapeutic target for the treatment of various pain conditions. Notably, various peptides isolated from venomous animals potently and selectively control the activation and inhibition of TRPV1 by binding to its outer pore region. This review will focus on the mechanisms by which venom-derived peptides interact with this portion of TRPV1 to control receptor functions and how these mechanisms can drive the development of new types of analgesics.

A Potential Route of Capsaicin to Its Binding Site in the TRPV1 Ion Channel.

Transient receptor potential (TRP) ion channels are important pharmacological targets because of their role in the perception of pain, and so, understanding their chemical regulation is essential for the development of analgesic drugs. Among the currently known TRP channel chemical agonists, capsaicin, the active compound of chili pepper, is probably the most exhaustively studied. The availability of the three-dimensional structure of the vanilloid receptor 1 (TRPV1) has fueled computational studies revealing the molecular details of capsaicin binding modes. Although this is a significant step, a comprehensible binding mechanism or pathway is invaluable for targeting TRP channels in modern pharmacology. In the present work, free-energy and enhanced sampling techniques have been used to explore a possible membrane-mediated pathway for capsaicin to enter the TRPV1 binding pocket where capsaicin accesses the protein starting at the extracellular milieu through the outer leaflet and into its binding site in the protein. The main states visited along this route have been characterized and include (i) a bound state in agreement with the binding mode “head-down, tail-up” and (ii) an alternative state corresponding to a “head-up, tail-down” binding mode. In agreement with previous reports, binding is mediated by both hydrogen bonds and van der Waals interactions, and residue Y511 is crucial for stabilizing the bound state and during the binding process. Together, these results provide a foundation to further understand TRPV channels, and they could be used to guide therapeutic design of selective inhibitors potentially leading to novel avenues for pharmacological applications targeting the TRPV1 channel.

Non-canonical endogenous expression of voltage-gated sodium channel NaV 1.7subtype by the TE671 rhabdomyosarcoma cell line.

The human TE671 cell line was originally used as a model of medulloblastoma but has since been reassigned as rhabdomyosarcoma. Despite the characterised endogenous expression of voltage‐sensitive sodium currents in these cells, the specific voltage‐gated sodium channel (VGSC) subtype underlying these currents remains unknown. To profile the VGSC subtype in undifferentiated TE671 cells, endpoint and quantitative reverse transcription–PCR (qRT‐PCR), western blot and whole‐cell patch clamp electrophysiology were performed. qRT‐PCR profiling revealed that expression of the SCN9A gene was ∼215‐fold greater than the SCN4A gene and over 400‐fold greater than any of the other VGSC genes, while western blot confirmed that the dominant SCN9A RNA was translated to a protein with a molecular mass of ∼250 kDa. Elicited sodium currents had a mean amplitude of 2.6 ± 0.7 nA with activation and fast inactivation V 50 values of −31.9 ± 1.1 and −69.6 ± 1.0 mV, respectively. The currents were completely and reversibly blocked by tetrodotoxin at concentrations greater than 100 nm (IC50 = 22.3 nm). They were also very susceptible to the NaV1.7 specific blockers Huwentoxin‐IV and Protoxin‐II with IC50 values of 14.6 nm and 0.8 nm, respectively, characteristic of those previously determined for NaV1.7. Combined, the results revealed the non‐canonical and highly dominant expression of NaV1.7 in the human TE671 rhabdomyosarcoma cell line. We show that the TE671 cell line is an easy to maintain and cost‐effective model for the study of NaV1.7, a major target for the development of analgesic drugs and more generally for the study of pain.Key points Undifferentiated TE671 cells produce a voltage‐sensitive sodium current when depolarised.The voltage‐gated sodium channel isoform expressed in undifferentiated TE671 cells was previously unknown. Through qRT‐PCR, western blot and toxin pharmacology, it is shown that undifferentiated TE671 cells dominantly (>99.5%) express the NaV1.7 isoform that is strongly associated with pain. The TE671 cell line is, therefore, a very easy to maintain and cost‐effective model to study NaV1.7‐targeting drugs.

Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability.

Cannabigerol (CBG), a non-psychotropic phytocannabinoid and a precursor of ∆9 -tetrahydrocannabinol and cannabidiol, has been suggested to act as an analgesic. A previous study reported that CBG (10μM) blocks voltage-gated sodium (Nav ) currents in CNS neurons, although the underlying mechanism is not well understood. Genetic and functional studies have validated Nav 1.7 channels as an opportune target for analgesic drug development. The effects of CBG on Nav 1.7 channels, which may contribute to its analgesic properties, have not been previously investigated. To determine the effects of CBG on Nav channels, we used stably transfected HEK cells and primary dorsal root ganglion (DRG) neurons to characterize compound effects using experimental and computational techniques. These included patch-clamp, multielectrode array, and action potential modelling. CBG is a ~10-fold state-dependent Nav channel inhibitor (KI -KR : ~2-20 μM) with an average Hill-slope of ~2. We determined that, at lower concentrations, CBG predominantly blocks sodium Gmax and slows recovery from inactivation. However, as the concentration is increased, CBG also induces a hyperpolarizing shift in the half-voltage of inactivation. Our modelling and multielectrode array recordings suggest that CBG attenuates DRG excitability. Inhibition of Nav 1.7 channels in DRG neurons may underlie CBG-induced neuronal hypoexcitability. As most Nav 1.7 channels are inactivated at the resting membrane potential of DRG neurons, they are more likely to be inhibited by lower CBG concentrations, suggesting functional selectivity against Nav 1.7 channels, compared with other Nav channels (via Gmax block).

Development of Effective and Safe Analgesic and Anti-Inflammatory Drugs: Harnessing Natural Substances for Clinical Solutions.

Development of Effective and Safe Analgesic and Anti-Inflammatory Drugs: Harnessing Natural Substances for Clinical Solutions.

Sedation-analgesia techniques for nonoperating room anesthesia: an update.

There has been a substantial increase in nonoperating room anesthesia procedures over the years along with an increase in the complexity and severity of cases. These procedures pose unique challenges for anesthesia providers requiring meticulous planning and attention to detail. Advancements in the delivery of sedation and analgesia in this setting will help anesthesia providers navigate these challenges and improve patient safety and outcomes. There has been a renewed interest in the development of newer sedative and analgesic drugs and delivery systems that can safely provide anesthesia care in challenging situations and circumstances. Delivery of anesthesia care in nonoperating room locations is associated with significant challenges. The advent of sedative and analgesic drugs that can be safely used in situations where monitoring capabilities are limited in conjunction with delivery systems, that can incorporate unique patient characteristics and ensure the safe delivery of these drugs, has the potential to improve patient safety and outcomes. Further research is needed in these areas to develop newer drugs and delivery systems.

The effects of vanilloid analogues structurally related to capsaicin on the transient receptor potential vanilloid 1 channel

Transient receptor potential vanilloid 1 (TRPV1) is known as a receptor of capsaicin, a spicy ingredient of chili peppers. It is also sensitive to a variety of pungent compounds and is involved in nociception. Here, we focused on the structural characteristics of capsaicin, and investigated whether vanillylmanderic acid (VMA), vanillic acid (VAcid), vanillyl alcohol (VAlc), vanillyl butyl ether (VBE), and vanillin, containing a vanillyl skeleton similar to capsaicin, affected the TRPV1 activities. For detection of TRPV1 activity, intracellular Ca2+ concentration ([Ca2+]i) was measured in HEK 293 cells heterologously expressing mouse TRPV1 (mTRPV1-HEK) and in mouse sensory neurons. Except for vanillin, four vanilloid analogues dose-dependently increased [Ca2+]i in mTRPV1-HEK. The solutions that dissolved VMA, VAcid and vanillin at high concentrations were acidic, whereas those of VAlc and VBE were neutral. Neutralized VAcid evoked [Ca2+]i increases but neutralized VMA did not. Mutation of capsaicin-sensing sites diminished [Ca2+]i responses to VAcid, VAlc and VBE. VAcid, VMA, and vanillin suppressed the activation of TRPV1 induced by capsaicin. VAcid and VMA also inhibited the acid-induced TRPV1 activation. In sensory neurons, VMA diminished TRPV1 activation by capsaicin or acids. The present data indicate that these structural characteristics of chemical compounds on TRPV1 may provide strategies for the development of novel analgesic drugs targeting nociceptive TRPV1.

New pharmacological strategies for analgesic drug development: focus on biased m opioid receptor agonists

New pharmacological strategies for analgesic drug development: focus on biased m opioid receptor agonists

Cannabigerol inhibits sodium conductance to reduce neuronal dorsal root ganglion excitability

Cannabigerol (CBG), a non-psychotropic phytocannabinoid, is a precursor for cannabis derivatives, Δ9-tetrahydrocannabinol and cannabidiol (CBD). Like CBD, CBG has been suggested as an analgesic. A previous study reported CBG (10 μM) blocks voltage-gated sodium (Nav) currents in CNS neurons. However, the manner in which CBG inhibits Nav channels, and whether this effect contributes to CBG's potential analgesic behavior remain unknown. Genetic and functional studies have validated Nav1.7 as an opportune target for analgesic drug development.

Retinoic Acid-Differentiated Neuroblastoma SH-SY5Y Is an Accessible In Vitro Model to Study Native Human Acid-Sensing Ion Channels 1a (ASIC1a).

Simple SummaryHuman neuroblastoma SH-SY5Y is used in neurobiology for studying various neuropathophysiological processes. In this study, we differentiated neuroblastoma cells into a neuronal-like phenotype with retinoic acid and studied if functional acid-sensing, transient receptor potential vanilloid-1 and ankyrin-1 ion channels were expressed in it. We found that homomeric acid-sensing ion channels 1a were expressed predominantly and yielded large ionic currents that can be modulated with different ligands. This channel plays important roles in synaptic plasticity, neurodegeneration, and pain perception. Thus, retinoic acid-treated neuroblastoma is a suitable model system for pharmacological testing on native human acid-sensing ion channels 1a. This approach can facilitate the development of new drugs for neuroprotection and pain management.Human neuroblastoma SH-SY5Y is a prominent neurobiological tool used for studying neuropathophysiological processes. We investigated acid-sensing (ASIC) and transient receptor potential vanilloid-1 (TRPV1) and ankyrin-1 (TRPA1) ion channels present in untreated and differentiated neuroblastoma SH-SY5Y to propose a new means for their study in neuronal-like cells. Using a quantitative real-time PCR and a whole-cell patch-clamp technique, ion channel expression profiles, functionality, and the pharmacological actions of their ligands were characterized. A low-level expression of ASIC1a and ASIC2 was detected in untreated cells. The treatment with 10 μM of retinoic acid (RA) for 6 days resulted in neuronal differentiation that was accompanied by a remarkable increase in ASIC1a expression, while ASIC2 expression remained almost unaltered. In response to acid stimuli, differentiated cells showed prominent ASIC-like currents. Detailed kinetic and pharmacological characterization suggests that homomeric ASIC1a is a dominant isoform among the present ASIC channels. RA-treatment also reduced the expression of TRPV1 and TRPA1, and minor electrophysiological responses to their agonists were found in untreated cells. Neuroblastoma SH-SY5Y treated with RA can serve as a model system to study the effects of different ligands on native human ASIC1a in neuronal-like cells. This approach can improve the characterization of modulators for the development of new neuroprotective and analgesic drugs.

Allium macrostemon Bunge. exerts analgesic activity by inhibiting NaV1.7 channel

Ethnopharmacological relevanceAllium macrostemon Bunge. is an edible Chinese herb traditionally used for the treatment of thoracic pain, stenocardia, heart asthma and diarrhea. Although its biological potential has been extensively proven such as antioxidant activity, antiplatelet aggregation, vasodilation and antidepressant-like activity, there are no reports in the literature regarding its pharmacological analgesic activity. Aim of the studyThe study was carried out to examine the anti-nociceptive activity of the crude extract of A. macrostemon bulbs and interpret its likely molecular target. Materials and methodsThe bulbs of A. macrostemon were gathered, dried-up, and extracted with water (AMWD). AMWD was subjected to activity testing, using chemical-induced (acetic acid and formalin test) and heat-induced (hot plate) pain models. To evaluate the likely mechanistic strategy involved in the analgesic effect of AMWD, whole-cell patch clamp recordings were conducted in acutely dissociated dorsal root ganglion (DRG) neurons and human embryonic kidney 293T (HEK293T) cells expressing pain-related receptors. Electrophysiological methods were employed to detect the action potentials of DRG neurons and potential targets of A. macrostemon. ResultsAMWD showed significant palliative effect in all heat and chemical induced pain assays. Moreover, AMWD significantly reduces the excitability of dorsal root ganglion neurons by reducing the firing frequency of action potentials. Further analysis revealed that voltage-gated sodium channel Nav1.7 is the potential target of A. macrostemon for its analgesic activity. ConclusionThis study has brought new scientific evidence of preclinical efficacy of A. macrostemon as an anti-nociceptive agent. Apparently, these effects are involved with the inhibition of the voltage-sensitive Nav1.7 channel contributing to the reduction of peripheral neuronal excitability. Our present study justifies the folkloric usage of A. macrostemon as a remedy for several pain states. Furthermore, A. macrostemon is a good resource for the development of analgesic drugs targeting Nav1.7 channel.

Pain Treatment in the Companion Canine Model to Validate Rodent Results and Incentivize the Transition to Human Clinical Trials.

One of the biggest challenges for analgesic drug development is how to decide if a potential analgesic candidate will work in humans. What preclinical data are the most convincing, incentivizing and most predictive of success? Such a predicament is not unique to analgesics, and the pain field has certain advantages over drug development efforts in areas like neuropsychiatry where the etiological origins are either unknown or difficult to ascertain. For pain, the origin of the problem frequently is known, and the causative peripheral tissue insult might be observable. The main conundrum centers around evaluation of translational cell- and rodent-based results. While cell and rodent models are undeniably important first steps for screening, probing mechanism of action, and understanding factors of adsorption, distribution metabolism and excretion, two questions arise from such studies. First, are they reliable indicators of analgesic performance of a candidate drug in human acute and chronic pain? Second, what additional model systems might be capable of increasing translational confidence? We address this second question by assessing, primarily, the companion canine model, which can provide particularly strong predictive information for candidate analgesic agents in humans. This statement is mainly derived from our studies with resiniferatoxin (RTX) a potent TRPV1 agonist but also from protein therapeutics using a conjugate of Substance P and saporin. Our experience, to date, is that rodent models might be very well suited for acute pain translation, but companion canine models, and other large animal studies, can augment initial discovery research using rodent models for neuropathic or chronic pain. The larger animal models also provide strong translational predictive capacity for analgesic performance in humans, better predict dosing parameters for human trials and provide insight into behavior changes (bladder, bowel, mood, etc.) that are not readily assessed in laboratory animals. They are, however, not without problems that can be encountered with any experimental drug treatment or clinical trial. It also is important to recognize that pain treatment is a major veterinary concern and is an intrinsically worthwhile endeavor for animals as well as humans.

Novel piperazine urea derivatives as highly potent transient receptor potential vanilloid 1 (TRPV1) antagonists

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high permeability to Ca2+, which can be activated by low pH, noxious heat and vanilloid compounds such as capsaicin. TRPV1 has been proved to be very important in the process of pain production and is considered to be a highly effective analgesic target. In this work, three series of new piperazine urea TRPV1 antagonists were designed, synthesized and evaluated based on classical TRPV1 antagonists BCTC and GRT12360. Among them, N-(4,6-dimethylpyridin-2-yl)-4-(2-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxamide (5ac) was finally identified, which had excellent TRPV1 antagonistic activity (IC50 (CAP) = 9.80 nM), good bioavailability and did not cause side effects of hyperthermia. In the study of molecular docking, the compound 5ac fitted well with the amino acid residues on rTRPV1 through hydrophobic interaction. Collectively, compound 5ac is an efficient TRPV1 antagonist and can be used as a candidate for the development of analgesic drugs.

TRPC5 and the path towards analgesic drug development

A recent study by Sadler et al. highlights transient receptor potential canonical 5 (TRPC5) as a potential target for treating pain conditions. This article discusses their findings in the context of analgesic drug development, an urgent pursuit required to combat the opioid crisis and help millions of people with chronic pain.

Evaluation of antinociceptive activity of Ilex dipyrena Wall. in mice

BackgroundIn order to find a new natural resource for pain-relief, the analgesic effects of Ilex dipyrena crude extract, fractions, and subfractions were evaluated in in-vivo mouse models with possible mechanism of action.MethodsAnalgesic effects of crude extract (100 and 200 mg/kg body weight), fractions and subfractions (75 mg/kg body weight) were screened using heat-induced (tail-immersion and hot plate test) and chemical-induced (formalin and acetic acid) nociception models in mice. The samples were also tested for the elucidation of a possible mechanism through opioidergic and GABAergic systems.ResultsThe administration of crude extract, fractions and subfractions produced analgesic responses in acetic acid, formalin, tail immersion, and hot plate model for pain similar to those obtained with the standard. Naloxone antagonized the antinociceptive effects of the tested samples, whereas bicuculline showed partial inhibition. Considering the analgesic response, crude extract, fractions, and subfractions demonstrated promising inhibitory activity against all test models for pain, which was further supported by the possible involvement of opioidergic and GABAergic systems.ConclusionThe results suggest that this plant may be useful in the development of new analgesic drugs. Further research with regard to the isolation of bioactive compounds is required to verify these findings.

Effects of Ketoprofen and Morphine on Pain‐Related Depression of Nestlet Shredding in Male and Female Mice

A primary goal in the treatment of pain is restoration of behaviors that are disrupted by pain. Preclinical pain researchers have attempted to develop procedures for evaluation of pain-related functional impairment in laboratory animals. The goal of the present study was to develop and validate a simple, low cost procedure for the objective evaluation of pain-related depression of home cage behavior in mice. On test days, a 5 × 5 cm Nestlet was weighed prior to being suspended from the wire lid of the home cage of individually housed male and female ICR mice. Over the course of experimental sessions, mice removed pieces of the suspended Nestlet, and began to build a nest with the material they removed. Thus, the weight of the pieces of Nestlet that remained suspended at various time points in the session provided an indicator of the rate of this behavior. The results indicate that Nestlet shredding was stable with repeated testing, and shredding was depressed by intraperitoneal injection of lactic acid. The nonsteroidal anti-inflammatory drug ketoprofen blocked pain-related depression of shredding, but did not block depression of shredding by a non-pain stimulus, the kappa opioid receptor agonist U69,593. These findings support the validity of this procedure for assessing the expression and treatment of pain-related functional impairment in mice. In contrast, the µ-opioid receptor agonist morphine did not block pain-related depression of shredding when tested up to doses that depressed shredding in the absence of lactic acid. This finding does not support the validity of this procedure for assessing the expression and treatment of pain-related functional impairment in mice. Two observations from the morphine experiments suggest further research with this procedure is warranted. First, unlike ketoprofen, morphine disrupted shredding when administered in the absence of lactic acid. Thus, it is possible that functional impairment produced by morphine is incompatible with antinociception as defined in this procedure, and manipulations that attenuate morphine-induced functional impairment might unmask antinociception. Second, the current study includes male and female mice, and the data from each sex were pooled for the primary analyses. When the data for male and female mice were segregated, the data suggest that studies designed and powered to examine sex differences might be worthwhile. For instance, males appear to be more sensitive to morphine-induced depression of shredding than females. The findings of the present study raise questions about the ability of this procedure to contribute to improvements in predictive validity in analgesic drug development, but the findings complement previous research on pain-related functional impairment. A growing body of research indicates that drug effects in the absence of pain-stimuli and the behavioral endpoint are key determinants of the effects of established analgesic drugs in these procedures. Understanding these and other behavioral and environmental variables will be an important component of efforts to improve translation from preclinical research to clinical application.

Antinociceptive evaluation of the aqueous bark extract of Zanthoxylum zanthoxyloides (Lam.) Zepern. and Timler (Rutaceae) on albino wistar rats

Objectives: This study aimed to investigate the phytochemistry and the analgesic activity of the aqueous bark extract of Zanthoxylum zanthoxyloides (AZZ) on albino Wistar rats. Methodology and Results: Phytochemical screening was done using colorimetric reactions and precipitations. Writhing, glutamate, and hot plate tests were used for antinociceptive assessment. The animals were given the extract (400 and 800 mg/kg) and standard drugs, orally. The phytochemical screening has revealed chemical components like alkaloids and flavonoids. The extract displayed significant antinociceptive activity (p < 0.05). At 400 and 800 mg/kg, the extract reduced the writhing by 33.51% and 54.74% respectively. Licking reduction was observed after 15 and 20 minutes of glutamate injection in groups that received extract at 800 and 400 mg/kg, respectively. For the hot plate test, the extract effect was obtained from the 30th to the 90th minutes. Conclusions and application of findings: This study finding corroborates the traditional use of Zanthoxylum zanthoxyloides species. This activity may be due to the presence of some chemical groups confirmed by the phytochemical screening such as flavonoids and alkaloids. The mechanism for the antinociceptive activity could be due to the inhibition of the synthesis of some inflammatory mediators such as prostaglandins and nitric oxide (NO). The plant Z. zanthoxyloides, particularly its bark, could be a potent source for the development of new analgesic drugs. Further researches about the safety and characterization of its effective ingredient are needed. Keywords: Albino Wistar rats, Zanthoxylum zanthoxyloides, bark, folk medicine, antinociceptive. 16495 Tougoma et al., J. Appl. Biosci. Vol.160:2021 Antinociceptive evaluation of the aqueous bark extract of Zanthoxylum zanthoxyloides (Lam.) Zepern. and Timler (Rutaceae) on albino wistar rats

Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies.

This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.