Alternatively, subtle mood dysregulation may be a risk-factor for riskier cannabis use consumption.Proposed theories accounting for these functional and behavioral differences in cannabis users may have multiple underlying etiologies.Chronic young adult cannabis users demonstrate abnormal CB1 receptor density in the ACC ; thus, frequent cannabis use may influence continued white matter myelination and gray matter pruning within this region, impacting structural integrity.Further, altering CB1 availability and eCB signaling may impact GABA and GLUT signaling, which is observed in the ACC of adolescents with chronic cannabis use , suggesting continued cannabis use may impact healthy ACC functioning.Indeed, rACC glutamate levels have been associated with interactions between task-positive and task-negative sub-regions , suggesting excitatory activity at rest may alter one’s ability to engage networks involved in environmental interaction.Thus, altered inhibitory eCB activity may account for changes in intrinsic ACC connectivity among users.It is also possible that abnormalities in rACC and increased symptoms of depression place adolescents and young adults at increased risk for regular cannabis use.Prospective longitudinal studies are needed to address causality.In terms of youth treatment, there are potential interventions that may target ACC functioning to improve emotional regulation and mood in cannabis users.For example, activation within the ACC was associated with positive treatment outcomes following change talk among a diverse group of cannabis-using youth.Mindfulness-based mediation and a combination of mindfulness with aerobic exercise have also been associated with ACC specific changes.Findings from the current study should be considered in light of potential limitations.Although comorbid use of nicotine products was measured, some participants may have smoked cannabis with nicotine mixed in ; this was not measured in the current study.Given the cross-sectional nature of the current study, potential differences in frontolimbic connectivity and sub-clinical mood symptoms may exist prior to the onset of frequent cannabis use and serve as a risk factor for regular cannabis grow equipment use during adolescence.The relationships between such factors and substance use patterns among youth have previously been investigated.
Therefore, prospective, longitudinal studies are necessary to determine timing and causality.In conclusion, the present multisite imaging study found that among otherwise healthy young adults devoid of independent mood or affective disorders, regular cannabis users had greater intrinsic connectivity between left and right rACC.The current study also found that greater intrinsic bilateral rACC connectivity was associated with greater sub-threshold depressive symptoms among cannabis users.Results coincide and expand uponprior intrinsic and task-based imaging projects among young adults with chronic cannabis use, suggesting altered connectivity between regions with high cannabinoid receptor density that are imperative for emotional inhibition, recognition, and regulation.As THC content continues to rise , today’s users may be at increased risk for elevated mood or anxiety symptoms.Considering these findings, it is recommended that youth delay regular use of cannabis until after peak brain maturation is achieved.In light of the current paper, cannabis interventions for youth may target improving anterior cingulate functioning, including aerobic exercise and mindfulness-based approaches [see ].Pain in Sickle Cell Disease is a major comorbidity and unique.It can arise from acute, unpredictable episodes of vaso-occlusive crises that may begin in infancy and continue throughout life.Additionally, chronic pain, with or without acute pain crises, occurs in a large proportion of SCD patients.In a study spanning just over 31,000 patient days, 232 adult SCD patients experienced chronic pain on more than 54% of total days.Acute, painful VOCs are a characteristic feature of SCD that require hospitalization, impair quality of life, and impact patient survival.Both acute as well as chronic pain are life disabling.Opioids are the mainstay for pain management in SCD, but high doses of opioids are required and are associated with adverse effects including pruritus, tolerance and opioid-induced hyperalgesia.Rates of opioid overdose are low in patients with SCD and have not shifted with the opioid epidemic.
Cannabinoids have been widely considered for treating pain to meet the demand for alternative pain management therapies.Evidence of human use of the Cannabis sativa L.plant in rituals and medicine dates back millennia.In 1970, cannabis was classified as a Schedule 1 drug in the United States , and it was deemed to have no known medical use and a high potential for abuse.Despite the prohibition of cannabis in the U.S.and many European countries, there has been steady progress in studying its constituents for their beneficial effects in many conditions.An analysis of cannabis use among people using opioids for chronic pain management reported greater pain relief with cannabis than with opioids used alone in a national survey of adults in the U.S..In addition, emerging evidence suggests that prescriptions for opioids and deaths attributed to opioid use have declined in states that have made medicinal cannabis legal.Sickle patients often report use of cannabis to manage pain.It will be an understatement to say that the opioid epidemic and Centres for Disease Control guidelines on opioid use in 2016 have added another hurdle to pain management in SCD because pain treatment for both persistent chronic and acute VOC pain is reliant on opioids.Surveys conducted on residents involved in pain management of SCD suggest that potential for opioid tolerance and dependence pose a major hurdle in prescribing opioids.Similarly, adults with SCD reported using cannabis due to increased stigmatization for seeking opioids for pain, recent inadequate opioid dosing by the prescribers, and lack of alternatives through healthcare providers.Similar challenges in opioid prescribing for pain management among providers and patients have been disruptive to lives of patients living with chronic pain in other conditions as well.Thus, inadequate pain management due to fear of opioid prescribing and dosing and stigmatization for continued requirement of opioids in SCD contribute to use of cannabis and related easily available products by the patients to find pain relief.On the other hand, it provides a compelling reason to evaluate the potential of cannabis and its many non-toxic products for the potential to treat sickle pain.Clinical pain management with opioids is presented in another review in this Special Issue and is thus not discussed in detail herein.Cannabinoids represent a promising alternative due to their tolerability and pre-clinical evidence for their efficacy in attenuating chronic and acute hyperalgesia in SCD.A recent prospective clinical trial of vaporized cannabis use in SCD also shows promise for cannabinoid use without any significant adverse events.
Hence, we discuss the mechanism-based understanding of using cannabinoids to treat pain based on pre-clinical and clinical observations in SCD.More importantly, we critically review the benefits and risks of cannabis use in the current environment flooded with “Medical Cannabis” and uncontrolled availability of cannabis products over the counter.We have used the word cannabis when cannabis has been used and cannabinoids as a general term for products derived from cannabis or synthetic cannabinoids.Cannabinoids comprise a broad class of plant-derived, synthetic, and endogenously produced compounds that act via cannabinoid receptors 1 and 2 and possibly others.The major plant-derived cannabinoids from Cannabis sativa L.are ∆9 -tetrahydrocannabinol and Cannabidiol.There also exists a class of endogenously produced cannabinoids, dubbed endocannabinoids ; the major eCBs are anandamide and 2-arachidonoyl-sn-glycerol , which are lipid-based signaling molecules that are produced on-demand.There has been a cascade of synthetic cannabinoids that act with higher potency than plant-derived and endogenous cannabinoids, which are invaluable research tools though many have potential for abuse.Cannabinoids exert their effects through interactions with the eCB system.The eCB system comprises the cannabinoid receptors, their endogenous ligands—the eCBs—and corresponding biosynthetic and degradative enzymes.Emerging strategies for leveraging the eCB system in various models of pain include targeting the enzymes responsible for production and breakdown of eCBs.The intoxicating effects of THC are mediated through activation of CB1R, which are concentrated in the central nervous system and are also expressed diffusely throughout the mammalian body.CB1R activation has been shown to modulate pain, appetite, cognition,emesis, reward , neuroexcitability, balance, thermoregulation and motor function.CB2R are expressed primarily on immune cells and display roles in regulating responses to pain, immune challenge, inflammation, and cell proliferation.CBD has been suggested to act via modulation of CB1R and/or other mechanisms, and we have previously discussed CBD for use in chronic pain.SCD originates from a single point mutation of the beta globin gene of hemoglobin that leads to rigid sickle-shaped red blood cells in a deoxygenated state.The biological underpinnings of pain in SCD remain poorly understood.Pain in SCD may be a direct consequence of avascular necrosis or lower limb ulcers.It is known that sickle RBCs cause vaso-occlusion leading to impaired blood and oxygen supply to the organs resulting in end-organ damage and acute, unpredictable and recurrent episodes of pain.Inflammation, endothelial activation, oxidative stress, ischemia/reperfusion injury, and hemolysis underlie sickle pathobiology, which are further enhanced in the wake of VOCs.The underlying mechanism for how vaso-occlusion leads to pain remains incompletely understood.In the last decade, strong pre-clinical findings have characterized chronic pain and the underlying key mechanisms that cause it.These include neurogenic and neuro inflammation,mobile grow system activation of transient receptor potential vanilloid 1, peripheral nerve damage, peripheral and central sensitization, spinal glial activation, increased blood–brain barrier permeability, mast cell activation, and Purkinje cell damage in the cerebellum.Neuroinflammation demonstrated with increased circulating substance P and glial fibrillary acidic protein and central sensitization have also been observed clinically.
Dorsal horn neurons in preclinical sickle models also demonstrated higher excitability in concert with activation of signaling pathways that promote neuronal excitability with increased GFAP-expressing astroglial cells and microglial activation.Therefore, humanized mouse models of SCD have provided mechanistic insights that mimic key features and mechanisms of pain observed clinically.The discovery of pain mediation by mast cells was the foremost demonstration of neuroimmune interactions affecting sickle pain.Inflammation and neuroinflammation arising from increased glial, neutrophil, monocyte, mast cell and neural activation and neurogenic inflammation underlie nerve injury leading to neuropathic pain, which may present non-uniformly in sickle patients as suggested by quantitative sensory testing.Hypersensitivity and lower threshold to mechanical and thermal stimuli on QST in patients with SCD may be due to injury to the peripheral and/or central nervous system, evoked by neuroinflammatory substances such as SP .Sickle patients have higher plasma levels of SP, tryptase and GFAP, markers of neuroinflammation.Tryptase is released from mast cell activation and sickle patients with acute myeloid leukemia benefited from mast cell inhibitor imatinib treatment exhibited by amelioration of VOC.In our preclinical studies, inhibiting mast cell activation with imatinib elicited significant analgesic response along with reduced expression of SP/calcitonin gene-related peptide , systemic inflammation, neurogenic inflammation and neuroinflammation.Our results indicated that activated mast cells in sickle micro-environment release tryptase eliciting SP and CGRP from peripheral nerve endings.Persistent mast cell activation in a feed-forward loop orchestrated by SP and other inflammatory mediators may contribute to the sustained sensitization of the peripheral nociceptors and consequently spinal neurons.Cannabinoids have been shown to inhibit mast cell activation, and therefore have the potential to ameliorate sickle pain and VOC.Stress-induced neuroinflammation was significantly attenuated in wild-type mice treated with JWH-133 and mice over expressing CB2R, but not in CB2R-knockout mice.Therefore, CB2R agonists augment CB1R analgesia in sickle pain, and both may be required to achieve effects similar to those from whole plant-based compounds found in cannabis.Cannabinoids attenuate inflammation, leukocyte trafficking and adhesion, mast cell activation, oxidative stress, ischemia/reperfusion injury and neurogenic inflammation via CB1Rs and CB2Rs.All these phenomena exacerbate pain and may underlie clinical features of SCD including impaired wound healing, renal damage, and retinopathy .Our finding that CP55,940 reduces hyperalgesia was associated with reduced mast cell activation, leukocyte counts and neurogenic inflammation.Severe inflammation in SCD is characterized by elevated cytokines, pro-inflammatory and vasoactive neuropeptides, in both humans and sickle mice.Microglial activation with significantly higher cytokine levels, toll-like receptor 4 expression and Stat3 phosphorylation in sickle mice spinal cords suggest a central inflammatory milieu.In animal models of diverse diseases, CB2R was found to mediate the anti-inflammatory effect of cannabinoids such as CBD, HU210, and WIN55,212-2, both peripherally and centrally.THC exhibits an anti-inflammatory effect that is mediated primarily through CB1Rs; however, CB2Rs do appear to play a critical role in regulating inflammation in most cellular and animal studies.Therefore, cannabinoids have the potential to target many mechanisms underlying pain in SCD and other comorbidities.Inflammation, hemolysis, and cell-free hemoglobin in the hypoxic sickle microenvironment cause oxidative stress in SCD.WIN55,212-2, CP55,940 and anandamide exert a protective effect on quinolinic acid-induced mitochondrial dysfunction, reactive oxygen species formation and lipid peroxidation in rat striated cultured cells and rat brain synaptosomes .Importantly, in parkin-null, human tau over expressing mice, a model of complex neurodegenerative disease, short-term Sativex administration significantly reduced intraneuronal monoamine oxidase-related free radicals, increased the ratio of reduced/oxidized glutathione, and improved behavioral and pathological abnormality.