Medication overuse headache following repeated morphine, but not [INCREMENT]9-tetrahydrocannabinol administration in the female rat.

 

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“The potential of [INCREMENT]-tetrahydrocannabinol (THC) as a treatment for migraine depends on antinociceptive efficacy with repeated administration.

Although morphine has good antinociceptive efficacy, repeated administration causes medication overuse headache (MOH) – a condition in which the intensity/frequency of migraine increases.

The present study compared the effect of repeated morphine or THC administration on the magnitude and duration of migraine-like pain induced by a microinjection of allyl isothiocyanate (AITC) onto the dura mater of female rats.

Acute administration of THC or morphine prevented AITC-induced depression of wheel running. This antinociception was maintained in rats treated repeatedly with THC, but not following repeated administration of morphine. Moreover, repeated morphine, but not THC administration, extended the duration of AITC-induced depression of wheel running.

These data indicate that tolerance and MOH develop rapidly to morphine administration. The lack of tolerance and MOH to THC indicates that THC may be an especially effective long-term treatment against migraine.”

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Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol

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“Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect. However, when given either intraperitoneally or orally as a purified product, a bell-shaped dose-response was observed, which limits its clinical use.
In the present study, we have studied in mice the anti-inflammatory and anti-nociceptive activities of standardized plant extracts derived from the Cannabis sativa L., clone 202, which is highly enriched in CBD and hardly contains any psychoactive ingredients.
In stark contrast to purified CBD, the clone 202 extract, when given either intraperitoneally or orally, provided a clear correlation between the anti-inflammatory and anti-nociceptive responses and the dose, with increasing responses upon increasing doses, which makes this plant medicine ideal for clinical uses.
The clone 202 extract reduced zymosan-induced paw swelling and pain in mice, and prevented TNFα production in vivo. It is likely that other components in the extract synergize with CBD to achieve the desired anti-inflammatory action that may contribute to overcoming the bell-shaped dose-response of purified CBD.
We therefore propose that Cannabis clone 202 (Avidekel) extract is superior over CBD for the treatment of inflammatory conditions.”  https://www.scirp.org/journal/PaperInformation.aspx?paperID=53912
“In conclusion, we recommend standardized plant extract of the Cannabis clone 202 for treatment of various inflammatory conditions.” https://file.scirp.org/Html/5-2500582_53912.htm
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Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons.

 Neuroscience

“Expression of cannabinoid 1 (CB1) and vanilloid 1 (VR1) receptor proteins was studied in adult, cultured rat dorsal root ganglion neurons. Immunostaining of CB1 receptors alone produced labelling in 57+/-2% of the cultured dorsal root ganglion neurons (n=3 cultures). The area of the labelled cells was between 200 and 800 microm(2) with an average of 527+/-68 microm(2). VR1 immunolabelling revealed immunopositivity in 42+/-6% of the total population of dorsal root ganglion neurons. Cells showing VR1-like immunopositivity had an area between 200 and 600 microm(2). The mean area of the VR1-like immunopositive neurons was 376+/-61 microm(2). Double immunostaining with antisera raised against the CB1 and VR1 receptor proteins, showed a high degree of co-expression between CB1 and VR1 receptors. An average of 82+/-3% of the CB1-like immunopositive cells also showed VR1-like immunoreactivity (n=3 cultures) while 98+/-2% of the VR1-like immunolabelled neurons showed CB1 receptor-like immunostaining (n=3 cultures). Our data suggests that nociceptive primary sensory neurons co-express CB1 and VR1 receptors to a very high degree. We propose that this may provide an anatomical basis for a powerful combination of VR1 mediated excitation and CB1-mediated inhibition of nociceptive responses at central and peripheral terminals of nociceptive primary afferents.”

https://www.ncbi.nlm.nih.gov/pubmed/11036202

https://www.sciencedirect.com/science/article/abs/pii/S0306452200003894

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Emerging Role of (Endo)Cannabinoids in Migraine.

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“In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain.

Individual sections of this review cover key aspects of this topic, such as: (i) the current knowledge on the endocannabinoid system (ECS) with emphasis on expression of its components in migraine related structures; (ii) distinguishing peripheral from central site of action of cannabinoids, (iii) proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv) therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v) dual (possibly opposing) actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors.

We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD) hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD) underlying the migraine aura.

Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components) or novel endocannabinoid therapeutics in migraine treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/29740328

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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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Opioids and cannabinoids interactions: involvement in pain management.

“Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems.

Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states.

Indeed, it is widely known that activation of either opioid or cannabinoid systems produce antinociceptive properties in different pain models.

Moreover, several biochemical, molecular and pharmacological studies support the existence of reciprocal interactions between both systems, suggesting a common underlying mechanism.

Further studies have demonstrated that the endogenous opioid system could be involved in cannabinoid antinociception and recent data have also provided evidence for a role of the endogenous cannabinoid system in opioid antinociception.

These interactions may lead to additive or even synergistic antinociceptive effects, emphasizing their clinical relevance in humans in order to enhance analgesic effects with lower doses and consequently fewer undesirable side effects.

Thus, the present review is focused on bidirectional interactions between opioids and cannabinoids and their potent repercussions on pain modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/20017728

http://www.eurekaselect.com/71318/article

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Interaction of the cannabinoid and opioid systems in the modulation of nociception

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“Cannabinoids and opioids produce antinociceptive synergy.

Cannabinoids such as Δ-9-tetrahydrocannabinol (THC) release endogenous opioids and endocannabinoids such as anandamide (AEA) also alter endogenous opioid tone.

Opioids and cannabinoids bind distinct receptors that co-localize in areas of the brain involved with the processing of pain signals. Therefore, it is logical to look at interactions of these two systems in the modulation of both acute and chronic pain.

This review summarizes the data indicating that with cannabinoid/opioid therapy one may be able to produce long-term antinociceptive effects at doses devoid of substantial side effects, while preventing the neuronal biochemical changes that accompany tolerance.

The clinical utility of modulators of the endocannabinoid system as a potential mimic for THC-like drugs in analgesia and tolerance-sparing effects of opioids is a critical future direction also addressed in the review.”

https://www.tandfonline.com/doi/abs/10.1080/09540260902782794

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Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids.

 

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“Cannabis has been used for millennia to treat a multitude of medical conditions including chronic pain.

Osteoarthritis (OA) pain is one of the most common types of pain and patients often turn to medical cannabis to manage their symptoms.

While the majority of these reports are anecdotal, there is a growing body of scientific evidence which supports the analgesic potential of cannabinoids to treat OA pain.

OA pain manifests as a combination of inflammatory, nociceptive, and neuropathic pain, each requiring modality-specific analgesics. The body’s innate endocannabinoid system (ECS) has been shown to ameliorate all of these pain subtypes.

This review summarizes the components of the ECS and details the latest research pertaining to plant-based and man-made cannabinoids for the treatment of OA pain. Recent pre-clinical evidence supporting a role for the ECS to control OA pain is described as well as current clinical evidence of the efficacy of cannabinoids for treating OA pain in mixed patient populations.

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β-Amyrin, the cannabinoid receptors agonist, abrogates mice brain microglial cells inflammation induced by lipopolysaccharide/interferon-γ and regulates Mφ1/Mφ2 balances.

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“Inflammation is a primary response to infection that can pathologically lead to various diseases including neurodegenerative diseases.

The purpose of this study was to evaluate the effect of β-Amyrin, a naturally occurring pentacyclic triterpenoid compound, on inflammation induced by lipopolysaccharide (LPS) and interferone-γ (IFN-γ) in rat microglial cells.

CONCLUSION:

β-Amyrin reduces inflammation in microglial cells and can be used as a potential anti-inflammatory agent in central nervous system neurodegenerative diseases such as Alzheimer and multiple sclerosis, by affecting the inflammatory cytokine and differentiation of microglia as resident CNS macrophages.”

https://www.ncbi.nlm.nih.gov/pubmed/29501766

“Amyrin and the endocannabinoid system. The canonical triterpene amyrin was recently suggested to bind to CB1 receptors and to significantly mediate cannabimimetic effects in animal models of pain.”   http://gertschgroup.com/blog/entry/3188293/amyrin-and-the-endocannabinoid-system

“The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting CB receptors”   https://www.researchgate.net/publication/225079976_The_antinociceptive_triterpene_b-amyrin_inhibits_2-arachidonoylglycerol_2-AG_hydrolysis_without_directly_targeting_CB_receptors

“Finally, pentacyclic triterpenes such as β-amyrin and cycloartenol have been shown to possess numerous biological activities including anti-bacterial, anti-fungal, anti-inflammatory and anti-cancer properties.” https://www.linkedin.com/pulse/cannabis-has-terpenes-say-what-pure-hempnotics

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Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability.

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“Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals.

Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability.

This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability.

Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis’s abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.”

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