OA is a painful joint disease that predominantly affects the elderly. Pain is the primary symptom of OA, and it can present as either intermittent or constant. OA pain mechanisms are complex and have only recently been determined. Both peripheral and central processes are involved in creating the OA pain experience, making targeted therapy problematic. Nociceptive, inflammatory and neuropathic pains are all known to occur in OA, but to varying degrees in a patient- and time-specific manner. A better understanding of these multifactorial components of OA pain will lead to the development of more effective and safer pain treatments.

Osteoarthritis: the genesis of pain.

Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a noneuphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine whether CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. Osteoarthritis was induced in male Wistar rats (150-175 g) by intra-articular injection of sodium monoiodoacetate (MIA; 3 mg). On day 14 (end-stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology, whereas pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 after MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300 μg) were assessed. In end-stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (P < 0.0001; n = 8). Acute, transient joint inflammation was reduced by local CBD treatment (P < 0.0001; n = 6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (P < 0.0001; n = 8), and was also found to be neuroprotective (P < 0.05; n = 6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.

/pdf/attenuation-of-early-phase-inflammation-by-cannabidiol-4zlovq2l19.pdf

Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis

ストレスによるラット脳内 Calcium/calmodulin dependent protein kinase II の発現量リン酸化およびリン酸化に関する検討

Resolvins are omega-3 fatty acid derived potent bioactive lipids that resolve inflammation and modulate transient receptor potential channels. Exogenous administration of the resolvin precursor 17-HDHA shows a strong analgesic effect in animal models of osteoarthritis and acute inflammatory pain, but has not been studied in humans. Our aim was to assess the role of 17-HDHA and resolvins in heat pain sensitivity and in osteoarthritis pain in humans. Resolvins D1, D2, D3, D5, E1 and 17-HDHA, were measured by liquid chromatography-mass spectrometry and tested for association with heat pain thresholds in 250 healthy volunteers who had undergone quantitative sensory testing. Resolvins D1, D2 and 17-HDHA were then tested in 62 individuals affected with knee osteoarthritis and 52 age matched controls and tested for association with knee pain. Circulating levels of docosahexaenoic acid (DHA) were also measured. Levels of 17-HDHA, but not those of the other 5 resolvins tested, were associated with increased heat pain thresholds (beta = 0.075; 95% CI 0.024, 0.126; p < 0.0046). 17-HDHA was associated with lower pain scores in OA patients (beta −0.41; 95% CI-0.69, −0.12; p < 0.005; adjusted for covariates) but not with radiographic osteoarthritis. The associations of 17-HDHA with heat pain sensitivity and osteoarthritis pain were independent of DHA levels.

/pdf/association-of-the-resolvin-precursor-17-hdha-but-not-d-or-e-1ffq35jddl.pdf

Association of the resolvin precursor 17-HDHA, but not D- or E- series resolvins, with heat pain sensitivity and osteoarthritis pain in humans.

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

Cardiac fibrosis, a known risk factor for heart disease, is typically caused by uncontrolled proliferation of fibroblasts and excessive deposition of extracellular matrix proteins in the myocardium. Cyclin-dependent kinase 1 (CDK1) is involved in the control of G2/M transit phase of the cell cycle. Here, we showed that isoproterenol (ISO)-induced cardiac fibrosis is associated with increased levels of CDK1 exclusively in fibroblasts in the adult mouse heart. Treatment of primary embryonic ventricular cell cultures with ISO (a nonselective β-adrenergic receptor agonist) increased CDK1 protein expression in fibroblasts and promoted their cell cycle activity. Quantitative PCR analysis confirmed that ISO increases CDK1 transcription in a transient manner. Further, the ISO-responsive element was mapped to the proximal −100-bp sequence of the CDK1 promoter region using various 5′-flanking sequence deletion constructs. Sequence analysis of the −100-bp CDK1 minimal promoter region revealed two putative nuclear fa...

A novel β-adrenergic response element regulates both basal and agonist-induced expression of cyclin-dependent kinase 1 gene in cardiac fibroblasts

There are sex differences in degenerative disease prevalence in humans. Most models of degenerative disease use male animals. Examining female and male responses to stress may give insight into disease prevalence. Heat shock proteins are chaperones linked to damaged proteins in degenerative diseases and may be expressed differentially in females and males. We have characterized the induced expression of Hsp27 and Hsp70 in the brain and the heart of female and male rats. Rats were heat shocked, brains were removed 24 h after, and western analyses were done to quantify the expression of these proteins. Immunofluorescence was used to localize Hsp70 and Hsp27 in the hippocampus. Overall, male rats have significantly greater induced expression of both Hsp27 and Hsp70 in the brain. In the hippocampus, Hsp27 was localized in astrocytes, and Hsp70 was localized in blood vessels and microglia, following heat shock. Therefore, the difference in expression of heat shock proteins seen in the brain of male and female rats following heat shock suggests that sex hormones may have an impact on degenerative disease prevalence.

Neurodegenerative Diseases, Sex Differences and the 27 kDa Heat Shock Protein in the Nervous System

kinase 1 gene in cardiac fibroblasts basal and agonist-induced expression of cyclin-dependent -adrenergic response element regulates both

There are over 100 different types of arthritis and each can differ greatly in their aetiology and pathophysiology; however, one characteristic that is common to all arthritic conditions is joint pain. Musculoskeletal pain is the leading cause of disability in the world, and the number one reason arthritis patients visit their primary care physician. Despite the prevalence and burden of arthritis pain, current analgesics lack sufficient efficacy and are plagued by multiple adverse side effects. In this review, we outline the current landscape of research concerning joint pain, drawing from both preclinical and clinical studies. Specifically, this review is a discussion of the different neurophysiological processes that occur during joint disease and how inflammatory and neuropathic aspects contribute to the development of arthritis pain.

Mechanisms and Mediators That Drive Arthritis Pain.

This study describes a medical school oncology interest group (OIG) and assesses its influence on student perceptions of oncology, interest in pursuing oncology as a career, and comfort levels with oncology topics such as breaking bad news. From 2015 to 2017, the OIG annual event took place at a satellite campus of a larger Canadian undergraduate medical school. The event provided a question and answer period with a panel of physicians from multiple oncology specialties-discussions focused around lifestyle, training, clinical work, lifestyle, and career focus. Small physician-led groups taught breaking bad news using the SPIKES framework. The interest group also provided a mentoring and networking opportunity to interested students. Pre- and post-event surveys were distributed to students and physicians. For three consecutive years, the student-run, and physician-mentored OIG successfully recruited student and physician participants, providing a clinical skill teaching session as well as mentorship opportunities to students. Pre-event surveys found that only 20% of students believed their current curriculum was adequate as it relates to oncology education. In pre-session, 13% (6/45) of students indicated comfort with the skill of breaking bad news, compared with that in post-session with 81% (34/42) of students feeling comfortable. When asked "How likely are you to pursue a future elective opportunity in oncology?" 49% (20/41) of students indicated "likely" as their response in the pre-session. This response increased post-session to 70% (28/40). The event highlighted the potential for OIGs to increase student interest in pursuing oncology electives and student-perceived comfort with breaking bad news. OIGs are important in promoting interest in the field of oncology and in improving confidence in breaking bad news. This medical student-created, run and maintained oncology interest group supplemented standard curriculum by providing relevant educational and mentorship opportunities to students. This study highlights the feasibility of implementing a self-sustaining medical school oncology interest group and its potential to positively impact student learning and interest in oncology.

Increasing Undergraduate Exposure to Oncology: the Role of Oncology Interest Groups.

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