Pain
-
Randomized Controlled Trial
A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain.
Over the last 2 decades, affirmative diagnoses of osteoarthritis (OA) in the United States have tripled due to increasing rates of obesity and an aging population. Hemp-derived cannabidiol (CBD) is the major nontetrahydrocannabinol component of cannabis and has been promoted as a potential treatment for a wide variety of disparate inflammatory conditions. Here, we evaluated CBD for its ability to modulate the production of proinflammatory cytokines in vitro and in murine models of induced inflammation and further validated the ability of a liposomal formulation to increase bioavailability in mice and in humans. ⋯ Liposomal CBD (20 mg/day) was as effective as the highest dose of nonliposomal CBD (50 mg/day) in improving clinical outcomes. Hematocrit, comprehensive metabolic profile, and clinical chemistry indicated no significant detrimental impact of CBD administration over the 4-week analysis period. This study supports the safety and therapeutic potential of hemp-derived CBD for relieving arthritic pain and suggests follow-up investigations in humans are warranted.
-
There is a well-established historical observation that structural joint damage by plain X-ray correlates poorly with symptomatic disease in osteoarthritis (OA). This is often attributed to the inability to visualise soft-tissue pathology within the joint and the recognition of heterogeneous patient factors that drive central pain sensitisation. A major issue is the relative paucity of mechanistic studies in which molecular pathogenesis of pain is interrogated in relation to tissue pathology. ⋯ Not only is the regulation of nerve growth factor within the joint being used to explore the relationship between tissue pathology and the origins of pain in OA, but it also provides a core model on which other molecules present within the joint can modulate the pain response. In this narrative review, how molecular and pathological tissue change relates to joint pain in OA will be discussed. Finally, a model for how tissue damage may lead to pain over the disease course will be proposed.
-
Single cell sequencing has provided unprecedented information about the transcriptomic diversity of somatosensory systems. Here, we describe a simple and versatile in situ hybridization (ISH)-based approach for mapping this information back to the tissue. We illustrate the power of this approach by demonstrating that ISH localization with just 8 probes is sufficient to distinguish all major classes of neurons in sections of the trigeminal ganglion. ⋯ Our results demonstrate that the surface of the eye and meninges are targeted by broad arrays of neural classes despite their very different sensory properties but exhibit idiotypic patterns of innervation at a quantitative level. Very surprisingly, itch-related neurons extensively innervated the meninges, indicating that these transcriptomic cell classes are not simply labeled lines for triggering itch. Together, these results substantiate the importance of a sensory neuron's peripheral and central connections as well as its transcriptomic class in determining its role in sensation.
-
High-threshold mechanosensitive and mechanoinsensitive ("silent") nociceptors have similar electrical thresholds for transcutaneous sine wave stimulation at 4 Hz that selectively activates cutaneous C nociceptors in human skin. Their fundamentally different functions particularly in chronic pain warrant differential stimulation protocols. We used transcutaneously delivered slow depolarizing stimuli (half-sine, 500 ms duration, 0.01-1 mA) in humans to assess intensity-response relations for the induction of pain psychophysically and recorded activation of mechanosensitive and silent nociceptors in healthy volunteers by microneurography. ⋯ In pig skin, the amplitude-dependent activation of mechanosensitive nociceptors was confirmed (0.2-1 mA, n = 28), and activation thresholds for most silent nociceptors (n = 13) were found above 10 mA. Non-nociceptive low-threshold mechanosensitive C fibers (n = 14) displayed lower activation thresholds for half-sine wave stimuli with an amplitude-dependent discharge increase between 0.01 and 0.1 mA. We conclude that transcutaneous electrical stimulation with 500-ms half-sine wave pulses between 0.2 and 1 mA causes amplitude-dependent pain by preferential activation of mechanosensitive C nociceptors.