Category Archives: Pain

The endocannabinoid system as a therapeutic target in neuropathic pain: a review

Posted on by
Reply
pubmed logo

“Introduction: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes.

Areas covered: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain.

Expert opinion: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39317147/

“Research on the modulation of the endocannabinoid system in nervous tissue related to neuropathic pain reveals complex mechanisms of pain modulation. Dysregulation of the endocannabinoid system, microglial activation, and interactions between various signaling pathways contribute to the onset and persistence of neuropathic pain. Understanding these molecular and cellular processes is crucial for developing targeted therapies that leverage the endocannabinoid system to alleviate neuropathic pain.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2024.2407824

“Smoked Cannabis Proven Effective In Treating Neuropathic Pain”

https://www.sciencedaily.com/releases/2007/10/071024141745.htm

Proof of Concept for High-Dose Cannabidiol Pretreatment to Antagonize Opioid Induced Persistent Apnea

Posted on by
Reply
pubmed logo

“Using a mouse equivalent of FDA-approved cannabidiol (CBD) dosing, we found high dose CBD affects opioid induced persistent apnea (OIPA), the principal cause of opioid related fatalities.

CBD pretreatment mitigated respiratory depression from fentanyl in awake mice and significantly delayed OIPA onset in anesthetized mice, effective as the opioid antagonist naloxone.

The powerful effect of CBD pretreatment on OIPA suggests a novel therapeutic strategy to reduce fatal opioid overdose incidence.”

https://pubmed.ncbi.nlm.nih.gov/39314412/

https://www.biorxiv.org/content/10.1101/2024.09.13.612358v1

“Naloxone is a life-saving medication that can reverse an overdose from opioids—including heroin, fentanyl, and prescription opioid medications—when given in time.”

https://www.cdc.gov/stop-overdose/caring/naloxone.html#:~:text=What%20is%20naloxone%3F,use%20and%20small%20to%20carry.

Cannabidiol for the Treatment of Cervical Spondyloarthritis-Related Pain: A Case Report

Posted on by
Reply
pubmed logo

“Spondyloarthritis (SA) is a chronic inflammatory disease that predominantly affects the spinal column. SA-related pain can be intense, persistent, and disabling. Studies with cannabis have been conducted involving patients with refractory epilepsy, multiple sclerosis, Parkinson’s disease, sleep disorders, and chronic pain.

Cannabidiol is the major non-psychotropic component of cannabis, has anti-inflammatory and analgesic properties, and exerts anxiolytic and mood-stabilizing effects. This paper reports a case of a 72-year-old male with SA, with mild stenoses of the spinal canal at C4-C5 and C5-C6 and stenoses of the left neural foramina at C3-C4, C4-C5, C5-C6, and C6-C7.

The use of cannabidiol in our patient achieved satisfactory results in the control of pain related to cervical spondyloarthritis.”

https://pubmed.ncbi.nlm.nih.gov/39295690/

https://www.cureus.com/articles/278440-cannabidiol-for-the-treatment-of-cervical-spondyloarthritis-related-pain-a-case-report#!/

Effectiveness of Cannabinoids Treatment in Pain Management and Other Fibromyalgia-Associated Symptoms: A Case Series

Posted on by
Reply

“Pharmacological therapies for FM are still ineffective in many patients, involving adverse effects that hinder their long-term use.

We aimed to assess the effectiveness of cannabinoids (Tilray Dried Flower THC18) in the management of chronic pain and other FM-associated symptoms according to patient-reported outcomes, in a series of three FM patients. 

We observed improvements after one and three months of cannabinoids treatment in Brief Pain Inventory (BPI), Visual Analogue Scale (VAS), Insomnia Severity Index (ISI), SF-36 Health Survey, and Fibromyalgia Impact Questionnaire (FIQ) allowing pain relief, and improvements in sleep quality, performance of daily life activities, and quality of life.

In conclusion, although more studies are needed, in our series of FM patients, cannabinoids treatment showed promising results in the management of chronic pain and other FM-associated symptoms, improving the quality of life of these patients.”

https://www.heraldopenaccess.us/openaccess/effectiveness-of-cannabinoids-treatment-in-pain-management-and-other-fibromyalgia-associated-symptoms-a-case-series

Opioid and Cannabinoid Systems in Pain: Emerging Molecular Mechanisms and Use in Clinical Practice, Health, and Fitness

Posted on by
Reply
pubmed logo

“Pain is an unpleasant sensory and emotional experience. Adequate pain control is often challenging, particularly in patients with chronic pain. Despite advances in pain management, drug addiction, overtreatment, or substance use disorders are not rare. Hence the need for further studies in the field.

The substantial progress made over the last decade has revealed genes, signalling pathways, molecules, and neuronal networks in pain control thus opening new clinical perspectives in pain management. In this respect, data on the epigenetic modulation of opioid and cannabinoid receptors, key actors in the modulation of pain, offered new perspectives to preserve the activity of opioid and endocannabinoid systems to increase the analgesic efficacy of opioid- and cannabinoid-based drugs.

Similarly, upcoming data on cannabidiol (CBD), a non-psychoactive cannabinoid in the marijuana plant Cannabis sativa, suggests analgesic, anti-inflammatory, antioxidant, anticonvulsivant and ansiolitic effects and supports its potential application in clinical contexts such as cancer, neurodegeneration, and autoimmune diseases but also in health and fitness with potential use in athletes. Hence, in this review article, we summarize the emerging epigenetic modifications of opioid and cannabinoid receptors and focus on CBD as an emerging non-psychoactive cannabinoid in pain management in clinical practice, health, and fitness.”

https://pubmed.ncbi.nlm.nih.gov/39273354/

https://www.mdpi.com/1422-0067/25/17/9407

Neuromolecular and behavioral effects of Cannabidiol on depressive-associated behaviors and neuropathic pain conditions in mice

Posted on by
Reply
pubmed logo

“Background and aims: Neuropathic pain (NP) has a high incidence in the general population, is closely related to anxiety disorders, and has a negative impact on the quality of life. Cannabidiol (CBD), as a natural product, has been extensively studied for its potential therapeutic effects on symptoms such as pain and depression (DP). However, the mechanism of CBD in improving NP with depression is not fully understood.

Methods: First, we used bioinformatics tools to deeply mine the intersection genes associated with NP, DP, and CBD. Secondly, the core targets were screened by Protein-protein interaction network, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, molecular docking and molecular dynamics simulation. Next, the effects of CBD intervention on pain and depressive behaviors in the spinal nerve ligation (SNL) mouse model were evaluated using behavioral tests, and dose-response curves were plotted. After the optimal intervention dose was determined, the core targets were verified by Western blot (WB) and Quantitative Polymerase Chain Reaction (qPCR). Finally, we investigated the potential mechanism of CBD by Nissl staining, Immunofluorescence (IF) and Transmission Electron Microscopy (TEM).

Results: A total of five core genes of CBD most associated with NP and DP were screened by bioinformatics analysis, including PTGS2, GPR55, SOD1, CYP1A2 and NQO1. Behavioral test results showed that CBD by intraperitoneal administration 5mg/kg can significantly improve the pain behavior and depressive state of SNL mice. WB, qPCR, IF, and TEM experiments further confirmed the regulatory effects of CBD on key molecules.

Conclusion: In this study, we found five targets of CBD in the treatment of NP with DP. These findings provide further theoretical and experimental basis for CBD as a potential therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/39245142/

“We identified five core genes associated with comorbid NP and DP targeted by CBD. CBD intervention can improve NP and depressive-associated behavior in mice.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390824003228?via%3Dihub


Perceptions in Orthopedic Surgery on the Use of Cannabis in Treating Pain: A Survey of Musculoskeletal Trauma Patients-Results From the Canadian POSIT Study

Posted on by
Reply
pubmed logo

“Objectives: To evaluate the patient-reported expectations regarding cannabis for pain following musculoskeletal (MSK) trauma and patients’ perceptions and attitudes regarding its use.

Design: A cross-sectional retrospective survey-based study.

Setting: Three orthopaedic clinics in Ontario (Level-1 trauma center, Level-2 trauma center, rehabilitation clinic).

Patients selection criteria: Adult patients presenting to the clinics from January 24, 2018, to March 7, 2018, with traumatic MSK injuries (fractures/dislocations and muscle/tendon/ligament injury) were administered an anonymous questionnaire on cannabis for MSK pain.

Outcome measures and comparisons: Primary outcome measure was the patients’ perceived effect of cannabis on MSK pain, reported on a continuous pain scale (0%-100%, 0 being no pain, and 100 unbearable pain). Secondary outcomes included preferences, such as administration route, distribution method, timing, and barriers (lack of knowledge, concerns for side effects/addiction, moral/religious opposition, etc.) regarding cannabis use.

Results: In total, 440 patients were included in this study, 217 (49.3%) of whom were female and 222 (50.5%) were male, with a mean age of 45.6 years (range 18-92 years, standard deviations 15.6). Patients estimated that cannabis could treat 56.5% (95% CI 54.0%-59.0%) of their pain and replace 46.2% (95% CI 42.8%-49.6%) of their current analgesics. Nearly one-third (131/430, 30.5%) reported that they had used medical cannabis and more than one-quarter (123/430, 28.6%) used it in the previous year. Most felt that cannabis may be beneficial to treat pain (304/334, 91.0%) and reduce opioid use (293/331, 88.5%). Not considering using cannabis for their injury (132/350, 37.7%) was the most common reason for not discussing cannabis with physicians. Higher reported pain severity (β = 0.2/point, 95% CI 0.1-0.3, P = 0.005) and previous medical cannabis use were associated with higher perceived pain reduction (β = 11.1, 95% CI 5.4-16.8, P < 0.001).

Conclusions: One in 3 orthopaedic trauma patients used medical cannabis. Patients considered cannabis could potentially be an effective option for managing traumatic MSK pain and believed that cannabis could reduce opioid usage following acute musculoskeletal trauma. These data will help inform clinicians discussing medical cannabis usage with orthopaedic trauma patients moving forward.”

https://pubmed.ncbi.nlm.nih.gov/39150305/

https://journals.lww.com/jorthotrauma/abstract/2024/09000/perceptions_in_orthopedic_surgery_on_the_use_of.12.aspx

THC vapor inhalation attenuates hyperalgesia in rats using a chronic inflammatory pain model

Posted on by
Reply
pubmed logo

“Humans use cannabinoid drugs to alleviate pain.

As cannabis and cannabinoids are legalized in the U.S. for medicinal and recreational use, it has become critical to determine the potential utilities and harms of cannabinoid drugs in individuals living with chronic pain.

Here, we tested the effects of repeated THC vapor inhalation on thermal nociception and mechanical sensitivity, in adult male and female Wistar rats using a chronic inflammatory pain model (i.e., treated with Complete Freund’s Adjuvant [CFA]).

We report that repeated THC vapor inhalation rescues thermal hyperalgesia in males and females treated with CFA, and also reduces mechanical hypersensitivity in CFA males but not females. Many of the anti-hyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure.

We also report plasma levels of THC and its major metabolites, some of which are cannabinoid type-1 receptor (CB1) agonists, after the first and tenth days of THC vapor inhalation. Finally, we report that systemic administration of the CB1 inverse agonist AM251 (1mg/kg; i.p.) blocks the anti-hyperalgesic effects of THC vapor in males and females.

These data provide a foundation for future work that will explore the cells and circuits underlying the anti-hyperalgesic effects of THC vapor inhalation in individuals with chronic inflammatory pain.

PERSPECTIVE: Cannabinoids are thought to have potential utility in the treatment of chronic pain, but few animal studies have tested the effects of chronic THC or cannabis in animal models of chronic pain. We tested the effects of repeated THC vapor inhalation on chronic pain-related outcomes in male and female animals.”

https://pubmed.ncbi.nlm.nih.gov/39121915/

https://www.jpain.org/article/S1526-5900(24)00599-6/abstract

Regulation of cannabinoid and opioid receptor levels by endogenous and pharmacological chaperones

Posted on by
Reply
pubmed logo

“Cannabinoid and opioid receptor activities can be modulated by a variety of posttranslational mechanisms including the formation of interacting complexes.

This study examines the involvement of endogenous and exogenous chaperones in modulating the abundance and activity of cannabinoid CB1 receptor (CB1R), delta opioid receptor (DOR), and CB1R-DOR interacting complexes.

Focussing on endogenous protein chaperones namely receptor transporter proteins (RTPs), we examined relative mRNA expression in the mouse spinal cord and found RTP4 to be expressed at higher levels compared to other RTPs. Next, we assessed the effect of RTP4 on receptor abundance by manipulating RTP4 expression in cell lines. Overexpression of RTP4 causes an increase and knock-down causes a decrease in the levels of CB1R, DOR, and CB1R-DOR interacting complexes; this is accompanied by parallel changes in signaling. The ability of small molecule lipophilic ligands to function as exogenous chaperones was examined using receptor-selective antagonists. Long term treatment leads to increases in receptor abundance and activity with no changes in mRNA supporting a role as pharmacological chaperones.

Finally, the effect of cannabidiol (CBD), a small molecule ligand and a major active component of Cannabis, on receptor abundance and activity in mice was examined. We find that CBD administration leads to increases in receptor abundance and activity in mouse spinal cord.

Together, these results highlight a role for chaperones (proteins and small molecules) in modulating levels and activity of CB1R, DOR, and their interacting complexes potentially through mechanisms including receptor maturation and trafficking. 

Significance Statement This study highlights a role for chaperones (endogenous and small membrane-permeable molecules) in modulating levels of CB1R, DOR, and their interacting complexes. These chaperones could be developed as therapeutics for pathologies involving these receptors.”

https://pubmed.ncbi.nlm.nih.gov/39103231/

https://jpet.aspetjournals.org/content/early/2024/08/05/jpet.124.002187

Analgesic properties of next generation modulators of endocannabinoid signaling: leveraging modern tools for the development of novel therapeutics

Posted on by
Reply
pubmed logo

“Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored.

In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and a/b-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action (MOA) and without intoxication.

We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG) hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor, GRABeCB2.0, may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level. 

Significance Statement Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, non-intoxicating, mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/39060165/

https://jpet.aspetjournals.org/content/early/2024/07/26/jpet.124.002119