The synthetic cannabinoid agonist WIN 55,212-2 reduces experimental pruritus via CB receptor activation.

Pruritus (i.e., the experience that evokes a desire to scratch) is an adaptive process that can become maladaptive, leading to a persistent scratch-itch cycle that potentiates pruritus and increases the risk of infection.

The Minor Phytocannabinoid Delta-8-Tetrahydrocannabinol Attenuates Collagen-Induced Arthritic Inflammation and Pain-Depressed Behaviors.

Patients with arthritis report using cannabis for pain management, and the major cannabinoid delta-9-tetrahydrocannabinol (Δ-THC) has anti-inflammatory properties, yet the effects of minor cannabinoids on arthritis are largely unknown. The goal of the present study was to determine the antiarthritic potential of the minor cannabinoid delta-8-tetrahydrocannabinol (Δ-THC) using the collagen-induced arthritis (CIA) mouse model. Adult male DBA/1J mice were immunized and boosted 21 days later with an emulsion of collagen and complete Freund's adjuvant.

Differential disruption of response alternation by precipitated Δ-THC withdrawal and subsequent Δ-THC abstinence in mice.

In addition to overt somatic symptoms, cannabinoid withdrawal can also manifest as disruptions in motivation and attention. Experimental animal models using operant-conditioning approaches reveal these differences, in either antagonist-precipitated or spontaneous withdrawal models. However, these processes have yet to be characterized in the same subjects simultaneously.

Monoacylglycerol Lipase Inhibition Using JZL184 Attenuates Paw Inflammation and Functional Deficits in a Mouse Model of Inflammatory Arthritis.

Patients with rheumatoid arthritis (RA) experience joint swelling and cartilage destruction resulting in chronic pain, functional disability, and compromised joint function. Current RA treatments, including glucocorticoid receptor agonists, produce adverse side effects and lack prolonged treatment efficacy. Cannabinoids (i.

Genetic deletion of in mice affects serotonin transporter expression and function and .

Background: Regulator of G protein Signaling (RGS) proteins inhibit G protein-coupled receptor (GPCR) signaling, including the signals that arise from neurotransmitter release. We have shown that RGS12 loss diminishes locomotor responses of C57BL/6J mice to dopamine transporter (DAT)-targeting psychostimulants. This diminution resulted from a brain region-specific upregulation of DAT expression and function in RGS12-null mice.

The short-acting synthetic cannabinoid AB-FUBINACA induces physical dependence in mice.

Background: Recent years have seen a rise in the diversity and use of synthetic cannabinoids. The present study evaluated the behavioral effects of the third-generation indazole-3-carboxamide-type synthetic cannabinoid, AB-FUBINACA.

Methods: Adult male and female C57BL/6J mice were treated with AB-FUBINACA (0-3 mg/kg, i.

Preclinical Testing of Nalfurafine as an Opioid-sparing Adjuvant that Potentiates Analgesia by the Mu Opioid Receptor-targeting Agonist Morphine.

Mu opioid receptor (MOR)-targeting analgesics are efficacious pain treatments, but notorious for their abuse potential. In preclinical animal models, coadministration of traditional kappa opioid receptor (KOR)-targeting agonists with MOR-targeting analgesics can decrease reward and potentiate analgesia. However, traditional KOR-targeting agonists are well known for inducing antitherapeutic side effects (psychotomimesis, depression, anxiety, dysphoria).

Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice.

Background: A subset of cannabis users develop some degree of Cannabis Use Disorder (CUD). Although behavioral therapy has some success in treating CUD, many users relapse, often citing altered sleep, mood, and irritability. Preclinical animal tests of cannabinoid withdrawal focus primarily on somatic-related behaviors precipitated by a cannabinoid receptor antagonist.

Selective and Context-Dependent Social and Behavioral Effects of Δ9-Tetrahydrocannabinol in Weakly Electric Fish.

Cannabinoid (CB) receptors are widespread in the nervous system and influence a variety of behaviors. Weakly electric fish have been a useful model system in the study of the neural basis of behavior, but we know nothing of the role played by the CB system. Here, we determine the overall behavioral effect of a nonselective CB receptor agonist, namely Δ9-tetrahydrocannabinol (THC), in the weakly electric fish Apte-ronotus leptorhynchus.

The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice.

Background And Purpose: Gabapentin is commonly prescribed for nerve pain but may also cause dizziness, sedation and gait disturbances. Similarly, inhibition of the endogenous cannabinoid enzyme monoacylglycerol lipase (MAGL) has antinociceptive and anti-inflammatory properties but also induces sedation in mice at high doses. To limit these side effects, the present study investigated the analgesic effects of coadministering a MAGL inhibitor with gabapentin.

The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain.

A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (that is, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol.

MAGL inhibition modulates gastric secretion and motility following NSAID exposure in mice.

Non-steroidal anti-inflammatory drugs (NSAIDs) are common analgesic drugs that also cause well-known, negative gastrointestinal (GI) side effects. The physiological mechanism(s) of NSAID-induced GI damage are unclear and are likely due to multiple causes. The most studied contributing mechanisms are increased gastric acid secretion and increased gastric motility.

Effects of a single night of postpartum sleep on childless women's daytime functioning.

Study Objectives: The maternal postpartum period is characterized by sleep fragmentation, which is associated with daytime impairment, mental health disturbances, and changes in melatonin patterns. In addition to sleep fragmentation, women undergo a complex set of physiological and environmental changes upon entering the postpartum period, confounding our understanding of effects of postpartum sleep disturbance. The primary study aim was to understand the basic impact of a single night of postpartum-like sleep fragmentation on sleep architecture, nocturnal melatonin levels, mood, daytime sleepiness, and neurobehavioral performance.

Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice.

Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy.

Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.

Cannabinoid receptor agonists, such as Δ(9)-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively.

Combined inhibition of monoacylglycerol lipase and cyclooxygenases synergistically reduces neuropathic pain in mice.

Background And Purpose: Neuropathic pain is commonly treated with GABA analogues, steroids or non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit one or more COX isozymes but chronic COX inhibition paradoxically increases gastrointestinal inflammation and risk of unwanted cardiovascular events. The cannabinoids also have analgesic and anti-inflammatory properties and reduce neuropathic pain in animal models.

Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models.

Unlabelled: Common pharmacological treatments of neuropathic and chronic inflammatory pain conditions generally lack efficacy and/or are associated with significant untoward side effects. However, recent preclinical data indicate that combined inhibition of cyclooxygenase (COX) and fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA), produces enhanced antinociceptive effects in a variety of murine models of pain. Accordingly, the primary objective of the present study was to investigate the consequences of co-administration of the COX inhibitor diclofenac and the highly selective FAAH inhibitor PF-3845 in models of neuropathic pain (i.

The endocannabinoid system modulates stress, emotionality, and inflammation.

The physiological and behavioral effects of stress are well characterized. Endocannabinoids are produced on demand and function to attenuate many of the physiological effects of the stress response. The endocannabinoid system is made up of cannabinoid receptors, the fatty acid signaling molecules that bind to and activate these receptors, and the enzymes that synthesize and catabolize these endocannabinoid signaling molecules.

Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice.

Complementary genetic and pharmacological approaches to inhibit monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), the primary hydrolytic enzymes of the respective endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, enable the exploration of potential therapeutic applications and physiologic roles of these enzymes. Complete and simultaneous inhibition of both FAAH and MAGL produces greatly enhanced cannabimimetic responses, including increased antinociception, and other cannabimimetic effects, far beyond those seen with inhibition of either enzyme alone. While cannabinoid receptor type 1 (CB1) function is maintained following chronic FAAH inactivation, prolonged excessive elevation of brain 2-AG levels, via MAGL inhibition, elicits both behavioral and molecular signs of cannabinoid tolerance and dependence.

Acute Δ(9)-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice.

Nonsteroidal anti-inflammatory drugs (NSAIDs), which are among the most widely used analgesics in the world, cause gastrointestinal inflammation that is potentially life-threatening. Although inhibitors of endocannabinoid catabolic enzymes protect against gastropathy in fasted NSAID-treated mice, the gastroprotective effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, have yet to be investigated. Male C57BL/6J mice were fasted, administered vehicle or Δ(9)-THC (.

Repeated low-dose administration of the monoacylglycerol lipase inhibitor JZL184 retains cannabinoid receptor type 1-mediated antinociceptive and gastroprotective effects.

The monoacylglycerol lipase (MAGL) inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) produces antinociceptive and anti-inflammatory effects. However, repeated administration of high-dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and cannabinoid receptor type 1 (CB1) downregulation and desensitization. This functional CB1 receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use.

Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation.

Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model.

Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice.

Fatty acid amide hydrolase (FAAH) is the primary degradative enzyme of the endocannabinoid anandamide (N-arachidonoylethanolamine), which activates cannabinoid CB(1) and CB(2) receptors. FAAH disruption reduces nociception in a variety of acute rodent models of inflammatory pain. The present study investigated whether these actions extend to the chronic, collagen-induced arthritis (CIA) model.

Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice.

Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively.

Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics, but can cause gastric and esophageal hemorrhages, erosion, and ulceration. The endogenous cannabinoid (endocannabinoid; eCB) system possesses several potential targets to reduce gastric inflammatory states, including cannabinoid receptor type 1 (CB(1)), cannabinoid receptor type 2 (CB(2)), and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184), a selective inhibitor of the primary catabolic enzyme of 2-AG, monoacylglycerol lipase (MAGL), would protect against NSAID-induced gastric damage.