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Medical cannabis is commonly and increasingly used by Canadians to manage chronic pain. As of March 2021, Health Canada reported that approximately 300,000 Canadians who were authorized to access medical cannabis, which is more than a 1000% increase from the 24,000 registered in 2015. Physicians, however, receive limited information on therapeutic cannabis during their training, and their perceptions regarding this therapeutic option are uncertain. This study focused on exploring attitudes and beliefs of pain physicians regarding medical cannabis for the management of chronic noncancer pain.
Learn More >Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) and . Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention.
Learn More >Bone-marrow mesenchymal stem cells (BM-MSCs) have not yet proven any significant therapeutic efficacy in spinal cord injury (SCI) clinical trials, due to the hostile microenvironment of the injured spinal cord at the acute phase. This study aims to modulate the inflammatory milieu by lipopolysaccharide (LPS) and granulocyte colony-stimulating factor (G-CSF) to improve the BM-MSCs therapy. For this purpose, we determined the optimum injection time and sub-toxic dosage of LPS following a T10 contusion injury. Medium-dose LPS administration may result in a local anti-inflammatory beneficial role. This regulatory role is associated with an increase in NF-200-positive cells, significant tissue sparing, and improvement in functional recovery compared to the SCI control group. The second aim was to examine the potential ability of LPS and LPS + G-CSF combination therapy to modulate the lesion site before BM-MSC (1 × 105 cells) intra-spinal injection. Our results demonstrated combination therapy increased potency to enhance the anti-inflammatory response (IL-10 and Arg-1) and decrease inflammatory markers (TNF-α and CD86) and caspase-3 compared to BM-MSC monotherapy. Histological analysis revealed that combination groups displayed better structural remodeling than BM-MSC monotherapy. In addition, Basso-Beattie-Bresnahan (BBB) scores show an increase in motor recovery in all treatment groups. Moreover, drug therapy shows faster recovery than BM-MSC monotherapy. Our results suggest that a sub-toxic dose of LPS provides neuroprotection to SCI and can promote the beneficial effect of BM-MSC in SCI. These findings suggest that a combination of LPS or LPS + G-CSF prior BM-MSC transplantation is a promising approach for optimizing BM-MSC-based strategies to treat SCI. However, because of the lack of some methodological limitations to examine the survival rate and ultimate fate of transplanted BM-MSCs followed by LPS administration in this study, further research needs to be done in this area. The presence of only one-time point for evaluating the inflammatory response (1 week) after SCI can be considered as one of the limitations of this study. We believed that the inclusion of additional time points would provide more information about the effect of our combination therapy on the microglia/macrophage polarization dynamic at the injured spinal cord.
Learn More >Total knee arthroplasty (TKA) is the final treatment option for patients with advanced knee osteoarthritis (OA). Unfortunately, TKA surgery is accompanied by acute postoperative pain that is more severe than arthroplasty performed in other joints. Elucidating the molecular mechanisms specific to post-TKA pain necessitates an animal model that replicates clinical TKA procedures, induces acute postoperative pain, and leads to complete functional recovery. Here, we present a new preclinical TKA model in rats and report on functional and behavioral outcomes indicative of pain, analgesic efficacy, serum cytokine levels, and dorsal root ganglia (DRG) transcriptomes during the acute postoperative period. Following TKA, rats exhibited marked deficits in weight bearing that persisted for 28 days. Home cage locomotion, rearing, and gait were similarly impacted and recovered by day 14. Cytokine levels were elevated on postoperative days one and/or two. Treatment with morphine, ketorolac, or their combination improved weight bearing while gabapentin lacked efficacy. When TKA was performed in rats with OA, similar functional deficits and comparable recovery time courses were observed. Analysis of DRG transcriptomes revealed upregulation of transcripts linked to multiple molecular pathways including inflammation, MAPK signaling, and cytokine signaling and production. In summary, we developed a clinically relevant rat TKA model characterized by resolution of pain and functional recovery within five weeks and with pain-associated behavioral deficits that are partially alleviated by clinically administered analgesics, mirroring the postoperative experience of TKA patients.
Learn More >The prevalence of chronic pain in children and adolescents is high. In some patients, it can be severe and refractory to conventional treatment options. There is increasing interest in the use of cannabinoids for therapeutic purposes in children and adolescents. Nabilone, a synthetic cannabinoid, is approved in Canada for the treatment of nausea and vomiting associated with chemotherapy. It can also be used off label for treatment of chronic pain.
Learn More >Knee osteoarthritis (OA) is a leading cause of disability in the elderly population. Chronic disabling pain is associated with maladaptive neuroplastic changes in brain networks, commonly associated with central sensitization. The main clinical features of nociplastic pain conditions include combined peripheral and central sensitization, and it is crucial to recognize this type of pain, as it responds to different therapies than nociceptive and neuropathic pain.
Learn More >Increasing evidence demonstrates 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) may be a safe and effective treatment for post-traumatic stress disorder (PTSD). There is growing interest in MDMA-AT to address a range of other health challenges. Chronic pain and PTSD are frequently comorbid, reciprocally interdependent conditions, though the possible role of MDMA-AT in treating chronic pain remains under-investigated. The present analysis examined the impact of manualized MDMA-AT on chronic pain severity among participants with PTSD who were enrolled in a Phase 2 clinical trial investigating MDMA-AT for PTSD (NCT03282123).
Learn More >To evaluate the efficacy of different non-pharmacologic therapies (NPTs) on relieving depressive symptoms and pain intensity in individuals living with chronic low back pain (LBP) and associated depression.
Learn More >Dorsal root ganglion stimulation (DRGS) is a neurostimulation therapy used to manage chronic pain that does not respond to conventional therapies. Unfortunately, not all patients receive sufficient pain relief from DRGS, leaving them with few other treatment options. Presently, our understanding of the mechanisms of action of DRGS is incomplete, preventing us from determining why some patients do not receive analgesia from the therapy. One hypothesis suggests that DRGS augments the filtering of action potentials (APs) at the T-junction of nociceptive C-neurons. To test this hypothesis, we utilized a computational modeling approach in which we developed a population of one thousand biophysically distinct C-neuron models which each produced electrophysiological characteristics (e.g., AP height, AP duration) reported in previous experimental studies. We used this population of model C-neurons to study how morphological and electrophysiological characteristics affected the propagation of APs through the T-junction. We found that trains of APs can propagate through the T-junction in the orthodromic direction at a higher frequency than in the antidromic direction due to the decrease in axonal diameter from the peripheral to spinal axon. Including slow outward conductances in the axonal compartments near the T-junction reduced following frequencies to ranges measured experimentally. We next used the population of C-neuron models to investigate how DRGS affected the orthodromic propagation of APs through the T-junction. Our data suggest that suprathreshold DRGS augmented the filtering of APs at the T-junction of some model C-neurons while increasing the activity of other model C-neurons. However, the stimulus pulse amplitudes required to induce activity in C-neurons (i.e., several mA) fell outside the range of stimulation pulse amplitudes used clinically (i.e., typically ≤1 mA). Furthermore, our data suggest that somatic GABA currents activated directly or indirectly by the DRGS pulse may produce diverse effects on orthodromic AP propagation in C-neurons. These data suggest DRGS may produce differential effects across a population of C-neurons and indicate that understanding how inherent biological variability affects a neuron's response to therapeutic electrical stimulation may be helpful in understanding its mechanisms of action.
Learn More >Acupuncture is commonly used as a treatment for migraines. Animal studies have suggested that acupuncture can decrease neuropeptides, immune cells, and proinflammatory and excitatory neurotransmitters, which are associated with the pathogenesis of neuroinflammation. In addition, acupuncture participates in the development of peripheral and central sensitization through modulation of the release of neuronal-sensitization-related mediators (brain-derived neurotrophic factor, glutamate), endocannabinoid system, and serotonin system activation. Clinical studies have demonstrated that acupuncture may be a beneficial migraine treatment, particularly in decreasing pain intensity, duration, emotional comorbidity, and days of acute medication intake. However, specific clinical effectiveness has not been substantiated, and the mechanisms underlying its efficacy remain obscure. With the development of biomedical and neuroimaging techniques, the neural mechanism of acupuncture in migraine has gained increasing attention. Neuroimaging studies have indicated that acupuncture may alter the abnormal functional activity and connectivity of the descending pain modulatory system, default mode network, thalamus, frontal-parietal network, occipital-temporal network, and cerebellum. Acupuncture may reduce neuroinflammation, regulate peripheral and central sensitization, and normalize abnormal brain activity, thereby preventing pain signal transmission. To summarize the effects and neural mechanisms of acupuncture in migraine, we performed a systematic review of literature about migraine and acupuncture. We summarized the characteristics of current clinical studies, including the types of participants, study designs, and clinical outcomes. The published findings from basic neuroimaging studies support the hypothesis that acupuncture alters abnormal neuroplasticity and brain activity. The benefits of acupuncture require further investigation through basic and clinical studies.
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