The role of cannabinoids in pain modulation in companion animals

Abstract

The use of cannabinoids in both veterinary and human medicine is controversial for legal and ethical reasons. Nonetheless, the availability and therapeutic use of naturally occurring or synthetic phytocannabinoids, such as Δ9-tetrahydrocannabidiol and cannabidiol, have been the focus of attention in studies regarding their medical uses. This review aims to examine the role of cannabinoids in pain modulation by analyzing scientific findings regarding the signaling pathways of the endocannabinoid system and discussing the analgesic effects of synthetic cannabinoids compared to cannabinoid extracts and the extent and involvement of their receptors. In animals, studies have shown the analgesic properties of these substances and the role of the cannabinoid binding −1 (CB1) and cannabinoid binding −2 (CB2) receptors in the endocannabinoid system to modulate acute, chronic and neuropathic pain. This system consists of three main components: endogenous ligands (anandamide and 2-arachidonoylglycerol), G protein-coupled receptors and enzymes that degrade and recycle the ligands. Evidence suggests that their interaction with CB1 receptors inhibits signaling in pain pathways and causes psychoactive effects. On the other hand, CB2 receptors are associated with anti-inflammatory and analgesic reactions and effects on the immune system. Cannabis extracts and their synthetic derivatives are an effective therapeutic tool that contributes to compassionate pain care and participates in its multimodal management. However, the endocannabinoid system interacts with different endogenous ligands and neurotransmitters, thus offering other therapeutic possibilities in dogs and cats, such is the case of those patients who suffer from seizures or epilepsy, contact and atopic dermatitis, degenerative myelopathies, asthma, diabetes and glaucoma, among other inflammatory diseases. Moreover, these compounds have been shown to possess antineoplastic, appetite-stimulating, and antiemetic properties. Ultimately, the study of the endocannabinoid system, its ligands, receptors, mechanism of action, and signaling, has contributed to the development of research that shows that hemp-derived and their synthetic derivatives are an effective therapeutic alternative in the multimodal management of pain in dogs and cats due to their ability to prevent peripheral and central sensitization.

Analgesic effects and metabolome analyses of laser- and electro-acupuncture combined therapies in paclitaxel-induced neuropathic pain model

“…The endocannabinoid system to which CB1R belongs is involved in the pain pathway and is composed of CB1R, CB2R, endocannabinoids such as transient receptor potential subfamily V member (TRPV) 1 and peroxisome proliferator-activated receptors (PPAR), and metabolizing enzymes ( 14 ). The endocannabinoid signaling system is regulated by synthesis and release of anandamide and 2-arachidonoylglycerol, uptake and degradation at supraspinal, spinal, and peripheral levels ( 8 , 14 , 35 ). Endocannabinoids are released activating CB1R, CB2R, and non-cannabinoid receptors including TRPV1 and PPAR ( 35 ).…”

“…Endocannabinoids are released activating CB1R, CB2R, and non-cannabinoid receptors including TRPV1 and PPAR ( 35 ). Released endocannabinoids are degraded by the hydrolyzing enzymes including FAAH and monoacylglycerol lipase, and by oxidative metabolism through cyclooxygenase, lipoxygenase and cytochrome P450 enzymes ( 8 , 35 ). The endocannabinoid signaling mechanisms for modulating pain are related to enhancing endocannabinoids levels by inhibiting enzymes and blocking their reuptake, so further large-scale research is required to evaluate the complex therapeutic roles of the endocannabinoid system in various pain-related diseases.…”

“…Neuronal pain processing, perception, and modulation have very complex mechanisms, and various proteins including cannabinoid receptor type 1 (CB1R) and fatty acid amide hydrolase (FAAH), c-Fos proto-oncogene (c-Fos), neuronal nuclear antigen (NeuN), and neuronal phosphoproteins, including synapsin I and microtubule-associated protein 2 (MAP2) are involved in the pain pathways ( 7 ). CB1R and FAAH belong to endocannabinoid system, which interacts with various endogenous ligands and neurotransmitters with neuroprotective, analgesic, and anti-inflammatory properties ( 8 ). c-Fos is present in neurons in response to stimulation, and synapsin 1 regulates synapse formation and neurotransmitter release ( 9 , 10 ).…”

Improved quality of life and pain relief in mature horses with osteoarthritis after oral transmucosal cannabidiol oil administration as part of an analgesic regimen

“…Among the latter, cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA) are prevalent. During heat extraction they are decarboxylated to cannabidiol (CBD) and 19-tetrahydrocannabinol (THC), which are the most widely used today for their potential medicinal applications (14)(15)(16)(17). Cannabidiol (CBD) is the second most important cannabinoid, after ∆9-tetrahydrocannabinol (THC).…”

“…This suggests a long elimination phase of CBD associated with a high volume of distribution to various tissues. Natural derivatives undergo hepatic hydroxylation, decarboxylation and conjugation, and may also be metabolized in extrahepatic tissues such as the small intestine lungs and brain (15)(16)(17). The analgesic properties of cannabinoids (CBD; THC) appear to be related to their lipophilic properties, which allow them to easily cross the blood-brain barrier and induce analgesia.…”