Accepted

Type I cannabinoid receptor (CB1R) has been reported to exhibit favorable anti-inflammation and anti-pruritus effects against inflammation-based skin diseases, but the specific mechanism remains to be explored. In this study, we found that the activation of CB1R significantly relieved the scratching behavior and skin inflammation in psoriatic mouse model, while CB1R antagonist aggravated these symptoms. As the expression of CB1R was abundant in dorsal root ganglia (DRG), we constructed mice with conditional CB1R knockout (CB1R-cKO) in primary sensory neurons and found that imiquimod (IMQ) induced psoriasiform inflammation and itch were both worsened in CB1R-cKO mice. Next, we observed that the CB1R mostly located in peptidergic neurons and deletion of CB1R in primary sensory neurons promoted the production and release of substance P (SP) to the skin tissue. Furthermore, the elevated SP in the skin affected the activation of ERK in keratinocytes and induced the accumulation of mast cells in the dermis. Last, we demonstrated that blocking the SP signal significantly alleviated the exacerbation of psoriasiform inflammation and itch caused by IMQ in CB1R-cKO mice. Together, our work reveals that CB1R in sensory neurons plays a key role in psoriasiform skin inflammation and pruritus via regulating SP expression.

In Woldeamanuel and Oliveira (2022)'s article about the efficacy of exercise in the treatment of migraine, the ranking of the efficacy of strength training (mean difference, - 3.55), aerobic exercise (mean difference, - 2.18 to - 3.13), topiramate (mean difference, - 0.98), and amitriptyline (mean difference, 3.82) using network meta-analysis can mislead readers. First, the inclusion criteria were reported at a monthly frequency of migraine and the end of the intervention, but some article did not meet the inclusion criteria or had data inconsistency. Second, there was an inconsistency in the placebos used in the included studies, which can be problematic in network meta-analysis. Third, all three articles on strength training were rated as high-risk or exhibited some risk of bias. Finally, the effectiveness of this statistical method is questionable for assessing physical activities because strength training, aerobic exercise, and preventive medications can be simultaneously recommended for possible synergistic effects in the prevention of migraine.

Deficient endogenous pain modulation has been implicated in the development and exacerbation of chronic orofacial pain. To date, relatively little is known regarding the function of the endogenous pain modulation in patients with burning mouth syndrome (BMS). This case-control study investigated endogenous pain modulation in women with BMS.

Neuropathic pain following spinal cord injury (SCI) remains a difficult problem that affects more than 80% of SCI patients. Growing evidence indicates that neuroinflammatory responses play a key role in neuropathic pain after SCI. Short hairpin RNA (shRNA) interference is an efficient tool for the knockdown of disease-related specific gene expression after SCI, yet insufficient data is available to establish guidelines. In this study, we have constructed the transient receptor potential ankyrin 1 (TRPA1) shRNA encoded-lentiviral vector (LV-shTRPA1) and P38 MAPK shRNA encoded-lentiviral vector (LV-shP38) to investigate the silencing effects of shRNAs and their ability to reprogram the neuroinflammatory responses, thereby enhancing somatosensory recovery after SCI. Our in vitro data employing HEK293-FT and activated macrophages demonstrated that delivered LV-shRNAs showed high transduction efficacy with no cytotoxicity. Furthermore, a combination of LV-shP38 and LV-shTRPA1 was found to be most effective at suppressing target genes, cutting the expression of pro-inflammatory and pro-nociceptive factors in the dorsal horn of the spinal cord and dorsal root ganglia, thus contributing to the alleviation of neuronal hypersensitivities after SCI. Overall, our data demonstrated that the combination LV-shP38/shTRPA1 produced a synergistic effect for immunomodulation and reduced neuropathic pain with a favorable risk-to-benefit ratio. Collectively, our LV-mediated shRNA delivery will provide an efficient tool for gene silencing therapeutic approaches to treat various incurable disorders.

Cryoneurolysis is an opioid-sparing therapy for long-lasting and reversible reduction of pain. We developed a nerve-selective method for cryoneurolysis by local injection of ice-slurry (- 5 to - 6 °C) that induced decrease in nocifensive response starting from about a week after treatment and lasting up to 8 weeks. In this study, we test the hypothesis that injection of colder slurry leads to faster onset of analgesia. Colder slurry (- 9ºC) was injected around the rat sciatic nerve to induce cryoneurolysis. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on surrounding tissues. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths. Functional tests were used to assess changes in sensory and motor function in the treated hind paw. No inflammation or scarring was detected in surrounding skin and muscle tissues at day 7 post slurry injection. Functional tests showed rapid onset reduction in mechanical pain sensitivity starting from day 1 and lasting up to day 98. CARS imaging demonstrated disintegration of myelin sheaths post treatment followed by complete recovery of nerve structure by day 140. In this study we showed that colder slurry (- 9 °C) produces more rapid onset and longer duration of analgesia, while remaining nerve-selective.

Treatment of neuropathic pain remains inadequate despite the elucidation of multiple pathophysiological mechanisms and the development of promising therapeutic compounds. The lack of success in translating knowledge into clinical practice has discouraged pharmaceutical companies from investing in pain medicine; however, new patient stratification approaches could help bridge the translation gap and develop individualized therapeutic approaches. As we highlight in this article, subgrouping of patients according to sensory profiles and other baseline characteristics could aid the prediction of treatment success. Furthermore, novel outcome measures have been developed for patients with neuropathic pain. The extent to which sensory profiles and outcome measures can be employed in routine clinical practice and clinical trials and across distinct neuropathic pain aetiologies is yet to be determined. Improvements in animal models, drawing on our knowledge of human pain, and robust public-private partnerships will be needed to pave the way to innovative and effective pain medicine in the future.

Chronic noncancer pain is a global public health challenge. It is imperative to identify biological markers ("biomarkers") to understand the mechanisms underlying chronic pain and to monitor pain over time and after interventions. Transcranial magnetic stimulation (TMS) is a promising method for this purpose.

Non-specific low back pain is a common, potentially disabling condition usually treated with self-care and non-prescription medication. For chronic low back pain, current guidelines recommend exercise therapy. Yoga is a mind-body exercise sometimes used for non-specific low back pain.

The use of perinatal-derived tissues and mesenchymal stromal cells (MSCs) as alternative treatment options to corticosteroid and hyaluronic acid injections has been gaining popularity. However, their ability to attenuate osteoarthritic (OA) symptoms while also slowing the progression of the disease remains controversial. Thus, the objective of this article is to summarize the results from both preclinical and clinical studies evaluating the efficacy of perinatal-derived tissue allografts and MSCs for the treatment of OA.