Acute pain is protective and a cardinal feature of inflammation. Chronic pain after arthritis, nerve injury, cancer, and chemotherapy is associated with chronic neuroinflammation, a local inflammation in the peripheral or central nervous system. Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. We review how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain. Recent studies also suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections. We also discuss new therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.

http://science.sciencemag.org/content/sci/354/6312/572.full.pdf

Pain regulation by non-neuronal cells and inflammation.

Rodents are commonly used to study the pathophysiological mechanisms of pain as studies in humans may be difficult to perform and ethically limited. As pain cannot be directly measured in rodents, many methods that quantify "pain-like" behaviors or nociception have been developed. These behavioral methods can be divided into stimulus-evoked or non-stimulus evoked (spontaneous) nociception, based on whether or not application of an external stimulus is used to elicit a withdrawal response. Stimulus-evoked methods, which include manual and electronic von Frey, Randall-Selitto and the Hargreaves test, were the first to be developed and continue to be in widespread use. However, concerns over the clinical translatability of stimulus-evoked nociception in recent years has led to the development and increasing implementation of non-stimulus evoked methods, such as grimace scales, burrowing, weight bearing and gait analysis. This review article provides an overview, as well as discussion of the advantages and disadvantages of the most commonly used behavioral methods of stimulus-evoked and non-stimulus-evoked nociception used in rodents.

/pdf/methods-used-to-evaluate-pain-behaviors-in-rodents-1i0wjp68s4.pdf

Methods Used to Evaluate Pain Behaviors in Rodents

Unending Work and Care: Managing Chronic Illness at Home

Molecular neurobiological insight into human nervous tissues is needed to generate next-generation therapeutics for neurological disorders such as chronic pain. We obtained human dorsal root ganglia (hDRG) samples from organ donors and performed RNA-sequencing (RNA-seq) to study the hDRG transcriptional landscape, systematically comparing it with publicly available data from a variety of human and orthologous mouse tissues, including mouse DRG (mDRG). We characterized the hDRG transcriptional profile in terms of tissue-restricted gene coexpression patterns and putative transcriptional regulators, and formulated an information-theoretic framework to quantify DRG enrichment. Relevant gene families and pathways were also analyzed, including transcription factors, G-protein-coupled receptors, and ion channels. Our analyses reveal an hDRG-enriched protein-coding gene set (∼140), some of which have not been described in the context of DRG or pain signaling. Most of these show conserved enrichment in mDRG and were mined for known drug-gene product interactions. Conserved enrichment of the vast majority of transcription factors suggests that the mDRG is a faithful model system for studying hDRG, because of evolutionarily conserved regulatory programs. Comparison of hDRG and tibial nerve transcriptomes suggests trafficking of neuronal mRNA to axons in adult hDRG, and are consistent with studies of axonal transport in rodent sensory neurons. We present our work as an online, searchable repository (https://www.utdallas.edu/bbs/painneurosciencelab/sensoryomics/drgtxome), creating a valuable resource for the community. Our analyses provide insight into DRG biology for guiding development of novel therapeutics and a blueprint for cross-species transcriptomic analyses.

Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq–based resource for pain and sensory neuroscience research

MCC950 a potent, highly specific small molecule inhibitor of canonical and noncanonical activation of NLRP3 inflammasome has been evaluated in a multitude of NLRP3 driven inflammatory diseases. However, the effect of MCC950 on colonic inflammation has not yet been reported. In the present study we investigated the effect of MCC950 in a spontaneous chronic colitis mouse model Winnie, which mimics human ulcerative colitis. Oral administration of 40 mg/kg MCC950 commencing at Winnie week seven for three weeks significantly improved body weight gain, colon length, colon weight to body weight ratio, disease activity index and histopathological scores. MCC950 significantly suppressed release of proinflammatory cytokines IL-1β, IL-18, IL1-α, IFNγ, TNF-α, IL6, IL17, chemokine MIP1a and Nitric Oxide in colonic explants. Moreover, MCC950 resulted in a significant decrease of IL-1β release and activation of caspase-1 in colonic explants and macrophage cells isolated from Winnie. Complete inhibition with MCC950 in Winnie colonic explants shows, for the first time, the contribution of inflammatory effects resulting exclusively from canonical and noncanonical NLRP3 inflammasome activation in colitis. Taken together, our results illustrate the efficacy of MCC950 in the treatment of murine ulcerative colitis and provides avenue for a potential novel therapeutic agent for human inflammatory bowel diseases.

/pdf/mcc950-a-specific-small-molecule-inhibitor-of-nlrp3-2gjeqxueg8.pdf

MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice.

Burn injury is a cause of significant mortality and morbidity worldwide and is frequently associated with severe and long-lasting pain that remains difficult to manage throughout recovery. We characterised a mouse model of burn-induced pain using pharmacological and transcriptomic approaches. Mechanical allodynia elicited by burn injury was partially reversed by meloxicam (5 mg/kg), gabapentin (100 mg/kg) and oxycodone (3 and 10 mg/kg), while thermal allodynia and gait abnormalities were only significantly improved by amitriptyline (3 mg/kg) and oxycodone (10 mg/kg). The need for relatively high opioid doses to elicit analgesia suggested a degree of opioid resistance, similar to that shown clinically in burn patients. We thus assessed the gene expression changes in dorsal root ganglion neurons and pathophysiological mechanisms underpinning burn injury-induced pain using a transcriptomic approach. Burn injury was associated with significantly increased expression of genes associated with axon guidance, neuropeptide signalling, behavioural defence response and extracellular signalling, confirming a mixed neuropathic and inflammatory aetiology. Notably, among the pain-related genes that were upregulated post-injury was the cholecystokinin 2 receptor (Cckbr), a G protein-coupled receptor known as a pain target involved in reducing opioid effectiveness. Indeed, the clinically used cholecystokinin receptor antagonist proglumide (30 mg/kg) was effective at reversing mechanical allodynia, with additional analgesia evident in combination with low-dose oxycodone (1 mg/kg), including significant reversal of thermal allodynia. These findings highlight the complex pathophysiological mechanisms underpinning burn injury-induced pain and suggest that cholecystokinin-2 receptor antagonists may be useful clinically as adjuvants to decrease opioid requirements and improve analgesic management.

Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target.

Background: Location-based augmented reality (AR) games, such as Pokemon GO and Harry Potter: Wizards Unite, have been shown to have a beneficial impact on the physical activity, social connectedness, and mental health of their players. In March 2020, global social distancing measures related to the COVID-19 pandemic prompted the AR games developer Niantic Inc to implement several changes to ensure continued player engagement with Pokemon GO and Harry Potter: Wizards Unite. We sought to examine how the physical and mental well-being of players of these games were affected during the unprecedented COVID-19 restriction period as well as how their video game engagement was affected.
Objective: The aims of this study were to examine the impact of COVID-19–related social restrictions on the physical and mental well-being of AR game players; to examine the impact of COVID-19–related social restrictions on the use of video games and motivations for their use; and to explore the potential role of AR games (and video games in general) in supporting well-being during COVID-19–related social restrictions.
Methods: A mixed methods web-based self-reported survey was conducted in May 2020, during which COVID-19–related social restrictions were enforced in many countries. Participants were recruited on the web via four subreddits dedicated to Pokemon GO or Harry Potter: Wizards Unite. Data collected included quantitative data on demographics, time spent playing video games, physical activity, and mental health; qualitative data included motivations to play and the impact of video games on mental health during COVID-19 lockdown.
Results: We report results for 2004 participants (1153/1960 male, 58.8%, average age 30.5 years). Self-reported physical activity during COVID-19–related social restrictions significantly decreased from 7.50 hours per week on average (SD 11.12) to 6.50 hours (SD 7.81) (P<.001). More than half of the participants reported poor mental health (925/1766, 52.4%; raw World Health Organization–5 Well-Being Index score <13). Female gender, younger age, and reduced exercise were significant predictors of poor mental health. Participants reported a significant increase in video game play time from 16.38 hours per week on average (SD 19.12) to 20.82 hours (SD 17.49) (P<.001). Approximately three quarters of the participants (n=1102/1427, 77.2%) reported that playing video games had been beneficial to their mental health. The changes made to Pokemon GO and Harry Potter: Wizards Unite were very well received by players, and the players continued to use these games while exercising and to maintain social connection. In addition to seeking an escape during the pandemic and as a form of entertainment, participants reported that they used video games for emotional coping and to lower stress, relax, and alleviate mental health conditions.
Conclusions: AR games have the potential to promote physical and mental health during the COVID-19 pandemic. Used by populations under isolation and distress, these games can improve physical and mental health by providing virtual socialization, sustained exercise, temporal routine, and mental structure. Further research is needed to explore the potential of AR games as digital behavioral interventions to maintain human well-being in the wider population.

/pdf/covid-19-as-game-changer-for-the-physical-activity-and-nwrxbgx20e.pdf

COVID-19 as 'Game Changer' for the Physical Activity and Mental Well-Being of Augmented Reality Game Players During the Pandemic: Mixed Methods Survey Study.

BackgroundDorsal root ganglion neuron-derived immortal cell lines including ND7/23 and F-11 cells have been used extensively as in vitro model systems of native peripheral sensory neurons. However,...

https://journals.sagepub.com/doi/pdf/10.1177/1744806916646111

Neuronal cell lines as model dorsal root ganglion neurons A transcriptomic comparison

Background: Dorsal root ganglion neuron-derived immortal cell lines including ND7/23 and F-11 cells have been used extensively as in vitro model systems of native peripheral sensory neurons. However, while it is clear that some sensory neuron-specific receptors and ion channels are present in these cell lines, a systematic comparison of the molecular targets expressed by these cell lines with those expressed in intact peripheral neurons is lacking. Results: In this study, we examined the expression of RNA transcripts in the human neuroblastoma-derived cell line, SHSY5Y, and two dorsal root ganglion hybridoma cell lines, F-11 and ND7/23, using Illumina next-generation sequencing, and compared the results with native whole murine dorsal root ganglions. The gene expression profiles of these three cell lines did not resemble any specific defined dorsal root ganglion subclass. The cell lines lacked many markers for nociceptive sensory neurons, such as the Transient receptor potential V1 gene, but expressed markers for both myelinated and unmyelinated neurons. Global gene ontology analysis on whole dorsal root ganglions and cell lines showed similar enrichment of biological process terms across all samples. Conclusions: This paper provides insights into the receptor repertoire expressed in common dorsal root ganglion neuronderived cell lines compared with whole murine dorsal root ganglions, and illustrates the limits and potentials of these cell lines as tools for neuropharmacological exploration.

Neuronal cell lines as model dorsal root ganglion neurons

https://espace.library.uq.edu.au/view/UQ:348269/UQ348269_OA.pdf

Kathleen Yin

Papers

Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target.

COVID-19 as 'Game Changer' for the Physical Activity and Mental Well-Being of Augmented Reality Game Players During the Pandemic: Mixed Methods Survey Study.

Neuronal cell lines as model dorsal root ganglion neurons A transcriptomic comparison

Neuronal cell lines as model dorsal root ganglion neurons

Therapeutic opportunities for targeting cold pain pathways.