Cannabinoid Modulation of Cutaneous Aδ Nociceptors During Inflammation

Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB1 and CB2). However, it is currently unknown if cannabinoids alter the response properties of nociceptors. In the present study, correlative behavioral and in vivo electrophysiological studies were conducted to determine if peripheral administration of the cannabinoid receptor agonists arachidonyl-2′-chloroethylamide (ACEA) or (R)-(+)-methanandamide (methAEA) could attenuate mechanical allodynia and hyperalgesia, and decrease mechanically evoked responses of Aδ nociceptors. Twenty-four hours after intraplantar injection of complete Freund's adjuvant (CFA), rats exhibited allodynia (decrease in paw withdrawal threshold) and hyperalgesia (increase in paw withdrawal frequency), which were attenuated by both ACEA and methAEA. The antinociceptive effects of these cannabinoids were blocked by co-administration with the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) but not with the CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl)methanone (AM630). ACEA and methAEA did not produce antinociception under control, non-inflamed conditions 24 h after intraplantar injection of saline. In parallel studies, recordings were made from cutaneous Aδ nociceptors from inflamed or control, non-inflamed skin. Both ACEA and methAEA decreased responses evoked by mechanical stimulation of Aδ nociceptors from inflamed skin but not from non-inflamed skin, and this decrease was blocked by administration of the CB1 receptor antagonist AM251. These results suggest that attenuation of mechanically evoked responses of Aδ nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB1 receptors during inflammation.

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Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

Molecules ◽

10.3390/molecules26113389 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3389

Author(s):

Ishtiaq Ahmed ◽

Saif Ur Rehman ◽

Shiva Shahmohamadnejad ◽

Muhammad Anjum Zia ◽

Muhammad Ahmad ◽

...

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Therapeutic Potential ◽

Endocannabinoid System ◽

Cell Types ◽

Autoimmune Disorders ◽

Specific Receptors ◽

Different Cell Types

In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer—both in vivo and in vitro clinical trials—has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.

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GPR18, GPR55 and GPR119 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f114/2019.4 ◽

2019 ◽

Vol 2019 (4) ◽

Author(s):

Stephen P.H. Alexander ◽

Andrew J. Irving

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Structural Similarity ◽

Synthetic Cannabinoid ◽

Receptor Ligands ◽

Orphan Status ◽

Endogenous Cannabinoid

GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [98]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.

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A selective EP4 receptor antagonist abrogates the stimulation of osteoblast recruitment from bone marrow stromal cells by prostaglandin E2 in vivo and in vitro

Bone ◽

10.1016/j.bone.2003.09.008 ◽

2004 ◽

Vol 34 (1) ◽

pp. 157-162 ◽

Cited By ~ 40

Author(s):

D Shamir ◽

S Keila ◽

M Weinreb

Keyword(s):

Bone Marrow ◽

Receptor Antagonist ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Ep4 Receptor ◽

Ep4 Receptor Antagonist ◽

Stimulation Of

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Spinal Cannabinoid Receptor Type 2 Activation Reduces Hypersensitivity and Spinal Cord Glial Activation after Paw Incision

Anesthesiology ◽

10.1097/01.anes.0000264765.33673.6c ◽

2007 ◽

Vol 106 (4) ◽

pp. 787-794 ◽

Cited By ~ 79

Author(s):

Alfonso Romero-Sandoval ◽

James C. Eisenach

Keyword(s):

Spinal Cord ◽

Side Effects ◽

Receptor Antagonist ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Intrathecal Injection ◽

Intrathecal Administration ◽

Glial Activation ◽

Receptor Agonists ◽

Cannabinoid 1 Receptor

Background Cannabinoids bind to cannabinoid receptors type 1 and 2 and produce analgesia in several pain models, but central side effects from cannabinoid 1 receptors limit their clinical use. Cannabinoid 2 receptors reduce inflammatory responses in the periphery by acting on immune cells, and they are present on glia in the central nervous system. This study tested whether spinal cannabinoid activation would induce analgesia, glial inhibition, and central side effects in a postoperative model or incisional pain. Methods Rats underwent paw incision surgery, with intrathecal injections of cannabinoid agonists and antagonists and assessment of withdrawal thresholds and behavioral side effects. Spinal glial activation was determined by immunohistochemistry. Results Intrathecal administration CP55940 reduced postoperative hypersensitivity (91 +/- 9% maximum possible effect; P < 0.05), and this was prevented by intrathecal administration of both cannabinoid 1 receptor (AM281) and cannabinoid 2 receptor (AM630) antagonists. CP55940 also caused several behavioral side effects, and these were prevented by the cannabinoid 1 receptor but not by the cannabinoid 2 receptor antagonist. Intrathecal injection of the cannabinoid 2 receptor agonist JWH015 reversed postoperative hypersensitivity (89 +/- 5% maximum possible effect; P < 0.05), and this was reversed by the cannabinoid 2 but not by the cannabinoid 1 receptor antagonist. JWH015, which did not induce behavioral side effects, reduced paw incision induced microglial and astrocytic activation in spinal cord (P < 0.05). Conclusions These data indicate that intrathecal administration of cannabinoid receptor agonists may provide postoperative analgesia while reducing spinal glial activation, and that selective cannabinoid 2 receptor agonists may do so without central side effects.

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Discovery of Orexant and Anorexant Agents with Indazole Scaffold Endowed with Peripheral Antiedema Activity

Biomolecules ◽

10.3390/biom9090492 ◽

2019 ◽

Vol 9 (9) ◽

pp. 492 ◽

Cited By ~ 5

Author(s):

Dimmito ◽

Stefanucci ◽

Pieretti ◽

Minosi ◽

Dvorácskó ◽

...

Keyword(s):

Feeding Behavior ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Methyl Esters ◽

Endocannabinoid System ◽

Tail Flick ◽

Binding Assays ◽

Tail Flick Test

The endocannabinoid system represents an integrated neuronal network involved in the control of several organisms’ functions, such as feeding behavior. A series of hybrids of 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (mimonabant), a well-known inverse agonist of the type-1 cannabinoid receptor (CB1), once used as an antiobesity drug, and the N-(2S)-substitutes of 1-[(4-fluorophenyl)methyl]indazole-3-carboxamide with 1-amino-3-methyl-1-oxobutane (AB-Fubinaca), 1-amino-3,3-dimethyl-1-oxobutane (ADB-Fubinaca), and 3-methylbutanoate (AMB-Fubinaca), endowed with potent agonistic activity towards cannabinoid receptors CB1 and CB2 were in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied by binding assays to cannabinoid receptors and by functional receptor assays, using rat brain membranes in vitro. The most active among them as an agonist, (S)-1-(2,4-dichlorobenzyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-1H-indazole-3-carboxamide (LONI11), and an antagonist, (S)-2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoic acid (LONI4), were tested in vivo in mic, to evaluate their ability to stimulate or suppress feeding behavior after intraperitoneal (i.p.) administration. For a LONI11 formalin test and a tail flick test after an administration by the subcutaneous (s.c.) and intracerebroventricular (i.c.v.) routes, respectively, were also carried out in vivo in mice to investigate the antinociceptive property at the central and peripheral levesl. We observed a significant orexant effect for LONI11 and an intense anorexant effect for (S)-methyl 2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (LONI2) and LONI4. In zymosan-induced edema and hyperalgesia, LONI11 reduced the percent of paw volume increase and paw latency after s.c. administration, also suggesting a possible peripheral anti-inflammatory activity.

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Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

Scientific Reports ◽

10.1038/s41598-021-90167-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ayat Zagzoog ◽

Asher L. Brandt ◽

Tallan Black ◽

Eunhyun D. Kim ◽

Riley Burkart ◽

...

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Partial Agonist ◽

Synthetic Cannabinoid ◽

Receptor Subtype ◽

Service Agency ◽

Subtype Selectivity ◽

Insight Into

AbstractThe first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

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Characterization of the vasorelaxation to methanandamide in rat gastric arteries

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y06-058 ◽

2006 ◽

Vol 84 (11) ◽

pp. 1121-1132 ◽

Cited By ~ 7

Author(s):

Joke Breyne ◽

Johan Van de Voorde ◽

Bert Vanheel

Keyword(s):

Smooth Muscle ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Relaxant Effect ◽

High K ◽

Calcitonin Gene ◽

Perivascular Nerves ◽

High Concentrations ◽

Stimulation Of

In the present study, the relaxant effect of the cannabinoid methanandamide was explored in rat gastric arteries. Since in some vessels cannabinoids have been shown to release calcitonin gene-related peptide (CGRP) from perivascular nerves, the influence of methanandamide was compared with that of exogenous CGRP. Methanandamide and CGRP elicited concentration-dependent, endothelium-independent relaxations. Methanandamide-induced relaxations were unaffected by the CB1 receptor antagonist AM251, the CB2 receptor antagonists AM630 and SR144528, and combined pre-exposure to AM251 and SR144528. Pre-exposure to O-1918, an antagonist of a novel nonCB1/nonCB2 cannabinoid receptor, did not influence the relaxations to methanandamide. Capsaicin or capsazepine treatment slightly inhibited methanandamide-induced relaxations. Preincubation with 30 mmol/L extracellular K+ or 3 mmol/L TEA had no significant effect on the responses elicited by methanandamide, but reduced CGRP-induced relaxations. Relaxation to 10−5 mol/L methanandamide was significantly blunted by Bay K8644 and by preincubation with nifedipine. Furthermore, 10−5 mol/L methanandamide significantly inhibited CaCl2-induced contractions in norepinephrine-stimulated vessels previously depleted of intra- and extracellular Ca2+. Finally, preincubation with 10−5 mol/L methanandamide almost completely abolished high K+-induced contractions. These findings suggest that the vasorelaxant action of methanandamide in rat gastric arteries is not mediated by stimulation of known cannabinoid receptors and only partly related to stimulation of TRPV1 receptors on perivascular nerves. At high concentrations, methanandamide might induce relaxation by reducing calcium entry into the smooth muscle cells.

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Peripheral Antinociception Induced by Aripiprazole Is Mediated by the Opioid System

BioMed Research International ◽

10.1155/2017/8109205 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Renata Cristina Mendes Ferreira ◽

Ana Flávia Almeida-Santos ◽

Igor Dimitri Gama Duarte ◽

Daniele C. Aguiar ◽

Fabricio A. Moreira ◽

...

Keyword(s):

Receptor Antagonist ◽

Opioid Receptor ◽

Antinociceptive Effect ◽

Opioid System ◽

Prostaglandin E ◽

Intraplantar Injection ◽

Opioid Receptor Antagonist ◽

Antinociceptive Effects ◽

The Right

Background. Aripiprazole is an antipsychotic drug used to treat schizophrenia and related disorders. Our previous study showed that this compound also induces antinociceptive effects. The present study aimed to assess the participation of the opioid system in this effect.Methods. Male Swiss mice were submitted to paw pressure test and hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2, 2 μg). Aripiprazole was injected 10 min before the measurement. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine, and bestatin were given 30 min before aripiprazole. Nociceptive thresholds were measured in the 3rd hour after PGE2injection.Results. Aripiprazole (100 μg/paw) injected locally into the right hind paw induced an antinociceptive effect that was blocked by naloxone (50 μg/paw), a nonselective opioid receptor antagonist. The role ofμ-,δ-, andκ-opioid receptors was investigated using the selective antagonists, clocinnamox (40 μg/paw), naltrindole (15, 30, and 60 μg/paw), and nor-binaltorphimine (200 μg/paw), respectively. The data indicated that only theδ-opioid receptor antagonist inhibited the peripheral antinociception induced by aripiprazole. Bestatin (400 μg), an aminopeptidase-N inhibitor, significantly enhanced low-dose (25 μg/paw) aripiprazole-induced peripheral antinociception.Conclusion. The results suggest the participation of the opioid system viaδ-opioid receptor in the peripheral antinociceptive effect induced by aripiprazole.

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Effect of cannabinoids on neural transmission in rat gastric fundus

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-005 ◽

2002 ◽

Vol 80 (1) ◽

pp. 67-76 ◽

Cited By ~ 51

Author(s):

M Storr ◽

E Gaffal ◽

D Saur ◽

V Schusdziarra ◽

H D Allescher

Keyword(s):

Smooth Muscle ◽

Receptor Antagonist ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Physiological Role ◽

Gastric Fundus ◽

Dependent Manner ◽

Receptor Agonists ◽

Relaxant Response ◽

Rat Gastric Fundus

The purpose of this study was to examine the possible role of cannabinoids on the neuromuscular function of rat gastric fundus. In addition to possible direct effects on smooth muscle, the influence of cannabinoids on contractile (cholinergic) and relaxant (non-adrenergic, non-cholinergic (NANC)) neural innervation of the rat gastric fundus was investigated in vitro. Neither anandamide (an endogenous cannabinoid receptor agonist) nor Win 55,212-2 and methanandamide (synthetic cannabinoid receptor agonists) nor AM 630 (a cannabinoid receptor antagonist) showed any effect on smooth muscle activity at baseline or after precontraction with 5-hydroxytryptamine (5-HT; 107 M). Electrical field stimulation (EFS) of the smooth muscle preparation (40 V; 5 Hz) caused cholinergically mediated twitch contractions that were abolished by atropine (106 M) or tetrodotoxin (TTX; 106 M). Anandamide and Win 55,212-2 reduced these twitch contractions in a concentration-dependent manner, an effect that could be reversed by the cannabinoid receptor antagonist AM 630 for anandamide, but not for Win 55,212-2. When NANC relaxant neural responses (presence of atropine (106 M) and guanethidine (106 M)) were induced by EFS, the cannabinoid receptor agonists anandamide and Win 55,212-2 reduced the relaxant response, an effect that could be reversed by the cannabinoid receptor antagonist AM 630 for anandamide, but not for Win 55,212-2. When given alone AM 630 caused an increase in the EFS-induced relaxant response. The presence of CB1 and CB2 cannabinoid receptor mRNA within the rat stomach was demonstrated by reverse transcription polymerase chain reaction (RT-PCR). The results of this study indicate that cannabinoids modulate excitatory cholinergic and inhibitory NANC neurotransmission in the rat gastric fundus. Endogenous cannabinoids may play a physiological role only in NANC inhibitory transmission, as AM 630 did not modify the electrically induced cholinergic contraction. The involved cannabinoid receptors are most likely located on neuronal structures. The present study also provides evidence that more than one receptor type is involved.Key words: cannabinoid, anandamide, rat gastric fundus relaxation, NANC, AM 630.

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