YokoCo

Preclinical pain research has applied state-of-the-art methods over the past 40 years to describe, characterize, and image molecules, cells, and circuits in rodents to understand the pathophysiology of chronic pain. Despite generating a plethora of novel analgesic targets, pharmaceuticals for chronic pain treatment remain largely limited to the same 6 drug classes as present 40 years ago. It is possible that 40 years of effort has brought us to the verge of a paradigm shift and an explosion of novel analgesic drug classes with remarkable safety, efficacy, and tolerability. We think it more likely that advances will not occur until we follow the description of exciting discoveries with hypothesis testing using clinically relevant preclinical animal models and ethologically relevant outcome measures, which better reflect the clinical characteristics of chronic pain syndromes. Furthermore, to be valuable, experiments using such models must be conducted to the highest levels of internal validity, rigor, and reproducibility. Efforts by funders, most recently the Helping End Addiction Long-Term by the National Institutes of Health, aim to address some of these challenges and enhance communication and collaboration between preclinical and clinical investigators. However, the greater problem is a culture that emphasizes novelty and number of publications over scientific rigor and robust replication leading to a high likelihood of false-positive results. A path forward is provided by the evolution of clinical research beginning 50 years ago that resulted in methods to reduce bias and enhance transparency and ethics of reporting, moving from case reports to randomized controlled trials to innovative study designs with a focus on rigor, generalizability, and reproducibility. We argue that culture changed in clinical science in part because powerful forces outside the peer review system, especially from federal regulators that approve new drugs and human studies committees that addressed ethical failures of earlier research, mandated change in studies within their purview. Whether an external force will affect change in peclinical pain research is unclear.

Pain relief by vibrotactile touch is a common human experience. Previous neurophysiological investigations of its underlying mechanism in animals focused on spinal circuits, while human studies suggested the involvement of supraspinal pathways. Here, we examine the role of primary somatosensory cortex (S1) in touch-induced mechanical and heat analgesia. We found that, in mice, vibrotactile reafferent signals from self-generated whisking significantly reduce facial nociception, which is abolished by specifically blocking touch transmission from thalamus to the barrel cortex (S1B). Using a signal separation algorithm that can decompose calcium signals into sensory-evoked, whisking, or face-wiping responses, we found that the presence of whisking altered nociceptive signal processing in S1B neurons. Analysis of S1B population dynamics revealed that whisking pushes the transition of the neural state induced by noxious stimuli toward the outcome of non-nocifensive actions. Thus, S1B integrates facial tactile and noxious signals to enable touch-mediated analgesia.

Pitavastatin is a competitive HMG-CoA reductase inhibitor for lowering of cholesterol level and low density lipoprotein cholesterol. This study was designed to evaluate the effect of pitavastatin in neuropathic pain induced by partial sciatic nerve ligation along with neuronal changes in Wister rats.

Morphine and other opioids are used to manage cancer-related pain; however, the role of these drugs in cancer progression remains controversial. Emerging evidence indicates that morphine can activate Toll-like receptor 4 (TLR4) and its signaling pathways, by the way the activation and expression of TLR4 can promote melanoma. In this study, we investigated the effects of morphine on the expression of TLR4 and promotion of melanoma in mice.

This prospective observational study included 80 adults (>18 years) patients admitted to the intensive care unit who were unconscious (Glasgow Coma Scale [GCS] score < 9 with a motor response < 5) and receiving mechanical ventilation. A tetanic stimulation was used to assess nociception; automated pupillometry (Algiscan, ID-MED, France) was used to compute the pupillary pain index score (PPI), with a PPI > 4 considered as nociception. Concomitantly, the number of skin conductance fluctuations (NSCF) per second, measured using a Skin Conductance Algesimeter (SCA, MEDSTORM Innovation AS, Norway; > 0.27 fluctuations/sec indicating nociception), and the instantaneous Analgesia Nociception Index (iANI, MDoloris Medical Systems, France; < 50 indicating nociception) were collected. Tetanic stimulation resulted in a median pupillary dilation of 16 [6-25] % and a PPI of 5 [2-7]. According to the PPI assessment, 44 patients (55%) had nociception, whereas 23 (29%) and 18 (23%) showed nociception according to the algesimeter and iANI assessment, respectively. No significant changes in measured physiologic variables were observed after the tetanic stimulation. There were no correlations between PPI, post-stimulation iANI, and SCA-derived variables. There were no differences in PPI, iANI, and SCA variables in patients with low and normal baseline EEG power at baseline. PERSPECTIVES: Detection of nociception varies across different devices in unconscious critically ill patients. Further studies are required to understand which method to implement for analgesic administration in this patient population.

Diabetic neuropathic pain (DNP) is a common, complex, and severe complication of diabetes. It can lead to increased mortality, lower-limb amputations, and distressing neuropathic symptoms. Available therapies for DNP are broad-spectrum analgesics, related to various side effects. Transient receptor potential vanilloid-1 (TRPV1) is widely expressed within the peripheral and central nervous systems and plays an essential role in pain perception and regulation. Both TRPV1 agonists and antagonists could reduce the sensitivity to nociception. Some exhibit blood glucose homeostasis regulates function by influencing insulin secretion and receptor sensitivity. Since TRPV1 has exhibited the unique advantages of simultaneously managing blood sugar and pain, developing new TRPV1 channel modulators for diabetes-related pain syndrome is a promising alternative to conventional therapy. In this review, the role of TRPV1 in the pathogenesis of DNP has been described and challenges of TRPV1 modulators have been explored to be a new therapy for DNP.

To identify predictors of acute treatment optimization with prescription drugs among people with episodic migraine.

Mounting evidence suggests that individuals who engage in nonsuicidal self-injury (NSSI) have lower pain sensitivity (e.g., pain thresholds and tolerances) than individuals without a history of NSSI. However, research has been largely cross-sectional, so it is unclear whether low pain sensitivity may increase risk for NSSI, or whether NSSI diminishes pain sensitivity over time. In the present study, the relations among NSSI frequency, versatility (number of NSSI methods), pain threshold, and pain tolerance were examined using a longitudinal research design. Participants included 156 undergraduate students at a large university (87% female; Mage = 19.79) with a recent history of NSSI. Participants reported on their NSSI engagement and completed a cold pressor task in a baseline session, as well as at one year follow-up. Eight regression models were run to examine the nature of the association between the two pain measures (i.e., pain threshold and tolerance) and the two NSSI measures (i.e., frequency and versatility). Pain tolerance and pain threshold predicted NSSI versatility over time, but NSSI frequency and versatility did not predict pain threshold or tolerance over time. Results suggest that low pain sensitivity may be a risk factor for severe NSSI engagement.

Our understanding of how peripheral damage-sensing neurons (nociceptors) respond to noxious stimuli is fundamental to the development of effective analgesics. To date, numerous studies have presented diverging hypotheses on how nociceptors encode modality-specific stimuli, including labelled-line, intensity dependence or pattern theory. In this short review, we appraise data from electrophysiological, behavioural, imaging and molecular expression studies from the last 60 years, in order to obtain a coherent view of modality-specific sensing in peripheral sensory neurons. We propose a mechanistic explanation for the broad range of values obtained for the incidence of polymodal nociceptors that reconciles apparently contradictory data.