Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation.

 Neuropharmacology

“Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects.

Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects.

Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy.

Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/29981335

https://www.sciencedirect.com/science/article/pii/S0028390818303575?via%3Dihub

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Evidence for the use of “medical marijuana” in psychiatric and neurologic disorders.

College of Psychiatric and Neurologic Pharmacists

“Cannabis is listed as a Schedule I substance under the Controlled Substances Act of 1970, meaning the US federal government defines it as an illegal drug that has high potential for abuse and no established medical use; however, half of the states in the nation have enacted “medical marijuana” (MM) laws. Clinicians must be aware of the evidence for and against the use of MM in their patients who may consider using this substance.

RESULTS:

Publications were identified that included patients with dementia, multiple sclerosis, Parkinson disease, Huntington disease, schizophrenia, social anxiety disorder, depression, tobacco use disorder, and neuropathic pain.

DISCUSSION:

There is great variety concerning which medical conditions are approved for treatment with MM for either palliative or therapeutic benefit, depending on the state law. It is important to keep an evidence-based approach in mind, even with substances considered to be illegal under US federal law. Clinicians must weigh risks and benefits of the use of MM in their patients and should ensure that patients have tried other treatment modalities with higher levels of evidence for use when available and appropriate.”

https://www.ncbi.nlm.nih.gov/pubmed/29955495

““Medical marijuana” encompasses everything from whole-plant cannabis to synthetic cannabinoids available for commercial use approved by regulatory agencies. In determining whether MM is of clinical utility to our patients, it is important to keep in mind chemical constituents, dose, delivery, and indication. Selection of the patient appropriate for MM must be carefully considered because clinical guidelines and treatment options with stronger levels of evidence should be exhausted first in most cases. There seems to be strongest evidence for the use of MM in patients with MS and in patients with neuropathic pain; moderate evidence exists to support further research in social anxiety disorder, schizophrenia, PD, and tobacco use disorder; evidence is limited for use in patients with dementia, Huntington disease, depression, and anorexia.”

http://mhc.cpnp.org/doi/10.9740/mhc.2017.01.029?code=cpnp-site

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An overview of the cannabinoid type 2 receptor system and its therapeutic potential.

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“This narrative review summarizes recent insights into the role of the cannabinoid type 2 (CB2) receptor as potential therapeutic target in neuropathic pain and neurodegenerative conditions.

RECENT FINDINGS:

The cannabinoid system continues to receive attention as a therapeutic target. The CB2 receptor is primarily expressed on glial cells only when there is active inflammation and appears to be devoid of undesired psychotropic effects or addiction liability. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases with limited or no currently approved therapies, such as neuropathic pain and neurodegenerative conditions such as Alzheimer’s disease.

SUMMARY:

The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/29794855

https://insights.ovid.com/crossref?an=00001503-900000000-98981

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Cannabinoid WIN-55,212-2 mesylate inhibits tumor necrosis factor-α-induced expression of nitric oxide synthase in dorsal root ganglion neurons.

 

“Tumor necrosis factor-α (TNF-α) is an established pain modulator in the peripheral nervous system. Elevated levels of TNF-α in dorsal root ganglion (DRG) neurons reportedly is critical for neuropathic pain processing. It has been shown that the production of nitric oxide, a key player in the development and maintenance of nociception, depends on the expression of nitric oxide synthases (NOSs) and their activities.

Accumulating evidence also supports an important role of cannabinoids in modulating neuropathic pain.

In this study, we explored the effects and the underlying mechanisms of crosstalk between TNF-α and cannabinoid on the expression/activity of NOS in DRG neurons.

Our findings suggest that TNF-α induces the expression/activity of nNOS in DRG neurons by increasing its mRNA stability by a p38 MAPK-dependent mechanism; WIN-55 inhibits this effect of TNF-α by inhibiting p38 MAPK via CB2.

By linking the functions of TNF-α, NOS and cannabinoid in DRG neurons, this study adds new insights into the molecular mechanisms underlying the pharmacologic effects of cannabinoids on neuropathic pain as well as into the pathophysiology of neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/29786105

https://www.spandidos-publications.com/10.3892/ijmm.2018.3687

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Endogenous systems involved in exercise-induced analgesia.

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“Exercise-induced analgesia is a phenomenon discussed worldwide. This effect began to be investigated in the early 1970s in healthy individuals and rodents during and after an acute or chronic session of running or swimming. Thereafter, studies found this effect was also induced by resistance exercises. Over the years, many studies have demonstrated the importance of exercise-induced analgesia in relieving pain caused by different conditions, such as fibromyalgia, low back pain, neuropathy, and osteoarthritis. This review aims to provide the reader with an in-depth description of the main endogenous systems, substances, neurotransmitters, receptors and enzymes that are thought to be involved in the analgesic effect induced by exercise. Many hypotheses have been proposed to elucidate the mechanisms responsible for exercise-induced analgesia. One of the most accepted hypotheses has been the activation of several endogenous systems described as analgesics. Studies have demonstrated that during and after exercise different endogenous systems are activated, which release substances or neurotransmitters, such as opioids, nitric oxide, serotonin, catecholamines and endocannabinoids, that may modulate the pain perception.”  https://www.ncbi.nlm.nih.gov/pubmed/29769416

http://www.jpp.krakow.pl/journal/archive/02_18/pdf/jpp.2018.1.01.pdf

“Exercise activates the endocannabinoid system.”  https://www.ncbi.nlm.nih.gov/pubmed/14625449

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Review of the neurological benefits of phytocannabinoids.

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“Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

METHODS:

In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.

RESULTS:

Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.

CONCLUSIONS:

In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/29770251

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

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Effects of cannabinoid type 2 receptor agonist AM1241 on morphine-induced antinociception, acute and chronic tolerance, and dependence in mice.

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“Morphine is a potent opioid analgesic used to alleviate moderate or severe pain but the development of drug tolerance and dependence limits its use in pain management.

Previous studies showed that cannabinoid type 2 (CB2) receptor ligands may modulate opioid effects. However, there is no report of the effect of CB2 receptor agonist on acute morphine tolerance and physical dependence. We therefore investigated the effect of a CB2 receptor agonist (AM1241) on morphine-induced morphine tolerance and physical dependence in mice.

Our findings suggest that coadministration of the CB2 receptor agonist and morphine could increase morphine antinociception and reduce morphine tolerance and physical dependence in mice.

PERSPECTIVE:

Combination of a CB2 agonist and morphine may provide a new strategy for better treatment of acute and chronic pain, and prevention of opioid tolerance and dependence. This may also provide a clue for the treatment of opioid tolerance and dependence in clinic.”

https://www.ncbi.nlm.nih.gov/pubmed/29729431

https://www.sciencedirect.com/science/article/pii/S1526590018301597

“Antinociceptive Synergy between 9 -Tetrahydrocannabinol and Opioids after Oral Administration” http://jpet.aspetjournals.org/content/jpet/304/3/1010.full.pdf

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Cannabinoid-Opioid Interaction in Chronic Pain

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“Cannabis inhalation with a vaporizer may enhance the analgesia of opioids.

In addition, previous research suggest that Cannabis may be useful in attenuating the development of opioid tolerance and dependence.

This is the first human study to show that inhaled cannabis safely potentiates the analgesia of opioids.

HUMAN STUDY SHOWS INHALED CANNABIS POTENTIATES ANALGESIA OF OPIOIDS.”

https://www.naturalmedicinejournal.com/journal/2012-06/cannabinoid-opioid-interaction-chronic-pain

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Antinociceptive Synergy between 9 -Tetrahydrocannabinol and Opioids after Oral Administration

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“Cannabinoids and opioids have been shown to possess several similar pharmacological effects, including analgesia

The analgesic effects of opioids, such as morphine and codeine, in mice are enhanced by oral administration of the cannabinoid 9 -tetrahydrocannabinol (9 -THC).

These findings suggest that the use of a low-dose combination of analgesics is a valid and effective approach for the treatment of pain and necessitates further study.

In summary, we have observed that 9 -THC enhances the antinociceptive effects of morphine and codeine in a synergistic fashion. This is the first report of a true synergistic interaction between oral 9 -THC and morphine or codeine, since previous studies have only examined one-dose combinations.

Much more work needs to be done to elucidate the mechanisms by which cannabinoids and opioids interact to produce analgesia. However, the implication that a combination of drugs may be more effective than either drug alone, and at the same time possibly reduce the occurrence of side effects, should provoke further study on analgesic drug interactions.”

http://jpet.aspetjournals.org/content/jpet/304/3/1010.full.pdf

http://healthdocbox.com/Substance_Abuse/71109245-Antinociceptive-synergy-between-9-tetrahydrocannabinol-and-opioids-after-oral-administration.html

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Molecular and cellular basis of cannabinoid and opioid interactions.

 Pharmacology Biochemistry and Behavior

“Cannabinoids and opioids have been shown to possess several similar pharmacological effects, including analgesia and stimulation of brain circuitry that are believed to underlie drug addiction and reward. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs.

The present review addresses the recent advances in the study of biochemical and molecular mechanisms underlying opioid and cannabinoid interaction. Several hypothesis have been formulated to explain this cross-modulation including the release of opioid peptides by cannabinoids or endocannabinoids by opioids and interaction at the level of receptor and/or their signal transduction mechanisms.

Moreover it is important to consider that the nature of cannabinoid and opioid interaction might differ in the brain circuits mediating reward and in those mediating other pharmacological properties, such as antinociception.

Further studies are needed since a better knowledge of the opioid-cannabinoid interaction may lead to exciting therapeutic possibilities.”

https://www.ncbi.nlm.nih.gov/pubmed/15927245

https://www.sciencedirect.com/science/article/pii/S0091305705001450?via%3Dihub

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