Increased burst coding in deep layers of the ventral anterior cingulate cortex during neuropathic pain

Neuropathic pain induces changes in neuronal excitability and synaptic connectivity in deep layers of the anterior cingulate cortex (ACC) that play a central role in the sensory, emotional and affective consequences of the disease. However, how this impacts ACC in vivo activity is not completely understood. Using a mouse model, we found that neuropathic pain caused an increase in ACC in vivo activity, as measured by the indirect activity marker c-Fos and juxtacellular electrophysiological recordings. The enhanced firing rate of ACC neurons in lesioned animals was based on a change in the firing pattern towards bursting activity. Despite the proportion of ACC neurons recruited by noxious stimuli was unchanged during neuropathic pain, responses to noxious stimuli were characterized by increased bursting. Thus, this change in coding pattern may have important implications for the processing of nociceptive information in the ACC and could be of great interest to guide the search for new treatment strategies for chronic pain.

Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans

In order to thrive in constantly changing environments, animals must adaptively respond to threatening events. Noxious stimuli are not only processed according to their absolute intensity, but also to their context. Adaptation processes can cause animals to habituate at different rates and degrees in response to permanent or repeated stimuli. Here, we used a forward genetic approach in Caenorhabditis elegans to identify a neuropeptidergic pathway, essential to prevent fast habituation and maintain robust withdrawal responses to repeated noxious stimuli. This pathway involves the FRPR-19A and FRPR-19B G-protein coupled receptor isoforms produced from the frpr-19 gene by alternative splicing. Loss or overexpression of each or both isoforms can impair withdrawal responses caused by the optogenetic activation of the polymodal FLP nociceptor neuron. Furthermore, we identified FLP-8 and FLP-14 as FRPR-19 ligands in vitro. flp-14, but not flp-8, was essential to promote withdrawal response and is part of the same genetic pathway as frpr-19 in vivo. Expression and cell-specific rescue analyses suggest that FRPR-19 acts both in the FLP nociceptive neurons and downstream interneurons, whereas FLP-14 acts from interneurons. Importantly, genetic impairment of the FLP-14/FRPR-19 pathway accelerated the habituation to repeated FLP-specific optogenetic activation, as well as to repeated noxious heat and harsh touch stimuli. Collectively, our data suggest that well-adjusted neuromodulation via the FLP-14/FRPR-19 pathway contributes to promote nociceptive signals in C. elegans and counteracts habituation processes that otherwise tend to rapidly reduce aversive responses to repeated noxious stimuli.

In silico Identification of Key Factors Driving the Response of Muscle Sensory Neurons to Noxious Stimuli

Nociceptive nerve endings embedded in muscle tissue transduce peripheral noxious stimuli into an electrical signal [i.e., an action potential (AP)] to initiate pain sensations. A major contributor to nociception from the muscles is mechanosensation. However, due to the heterogeneity in the expression of proteins, such as ion channels, pumps, and exchangers, on muscle nociceptors, we currently do not know the relative contributions of different proteins and signaling molecules to the neuronal response due to mechanical stimuli. In this study, we employed an integrated approach combining a customized experimental study in mice with a computational model to identify key proteins that regulate mechanical nociception in muscles. First, using newly collected data from somatosensory recordings in mouse hindpaw muscles, we developed and then validated a computational model of a mechanosensitive mouse muscle nociceptor. Next, by performing global sensitivity analyses that simulated thousands of nociceptors, we identified three ion channels (among the 17 modeled transmembrane proteins and four endoplasmic reticulum proteins) as potential regulators of the nociceptor response to mechanical forces in both the innocuous and noxious range. Moreover, we found that simulating single knockouts of any of the three ion channels, delayed rectifier voltage-gated K+ channel (Kv1.1) or mechanosensitive channels Piezo2 or TRPA1, considerably altered the excitability of the nociceptor (i.e., each knockout increased or decreased the number of triggered APs compared to when all channels were present). These results suggest that altering expression of the gene encoding Kv1.1, Piezo2, or TRPA1 might regulate the response of mechanosensitive muscle nociceptors.

Case report: Perioperative management of a patient with familial dysautonomia

Familial dysautonomia is a rare autosomal recessive neurodegenerative disease affecting cells of the autonomic nervous system. Patients with this disease are insensitive to pain but their autonomic nervous system is still activated with noxious stimuli. This report details a case of a patient with familial dysautonomia who underwent right ankle open reduction and internal fixation for a bimalleolar right ankle fracture. The patients preoperative and intraoperative course were uneventful but shortly after handoff to the intensive care unit, the patient experienced an autonomic crisis. Management of these patients is complex, requiring maintenance of physiologic homeostasis as well as preventing hemodynamic instability caused by noxious stimuli. Any deviations from baseline may cause an autonomic crisis, as happened in our patient. Herein, we detail the perioperative management of a patient with familial dysautonomia in further detail.

Premature infants display discriminable behavioural, physiological and brain responses to noxious and non-noxious stimuli

Pain assessment in preterm infants is challenging, as behavioural, autonomic and neurophysiological measures of pain are reported to be less sensitive and specific than in term infants. Understanding the pattern of preterm infants’ noxious-evoked responses is vital to improve pain assessment in this group. This study investigated the discriminability and development of multi-modal noxious-evoked responses in infants aged 28-40 weeks postmenstrual age. A classifier was trained to discriminate responses to a noxious heel lance from a non-noxious control in 47 infants, using measures of facial expression, brain activity, heart rate and limb withdrawal, and tested in two independent cohorts with a total of 98 infants. The model discriminates responses to the noxious from the non-noxious procedure from 28 weeks onwards with an overall accuracy of 0.77-0.83 and an accuracy of 0.78-0.79 in the 28-31 week group. Noxious-evoked responses have distinct developmental patterns. Heart rate responses increase in magnitude with age, while noxious-evoked brain activity undergoes three distinct developmental stages, including a previously unreported transitory stage consisting of a negative event-related potential between 30-33 weeks postmenstrual age. These findings demonstrate that while noxious-evoked responses change across early development, infant responses to noxious and non-noxious stimuli are discriminable from 28 weeks onwards.

Midwifery Care for Postpartum Mothers with Discomfort Pain of Episiotomy Stitches at PMB Ernyadi Sidoarjo

The pain due to the episiotomy is not the same, the intensity of the pain is different. This pain is due to the active peripheral nociceptors, which are receptors in particular, which are responsible for delivering to noxious stimuli. This midwifery care is aimed at dealing with complints to Mrs.P history of episiotomy at BPM Ernyadi Sidoarjo with the method of collecting initial data to evaluation the results obtained by Mrs.P a history of episiotomy. Did not find any difficulties at the time the care was given this study was carried out at 2 hours of the puerperium the mother gave birth on January 12, 2020 at 19.15 spontaneously an episiotomy was carried out on the indication of a stiff perineum according to the theory the conclusion from the case study with the initial data collection method to the eva;uation of the problem Mrs.P all the findings and all the actions that have been implemented, Mrs there was no difference between the theory and no signs of infection in the episiotomy suture scars.

Age Differences in Multi-modal Quantitative Sensory Testing and Associations with Brain Volume

Background and Objectives Somatosensory function is critical for successful aging. Prior studies have shown declines in somatosensory function with age; however, this may be impacted by testing site, modality, and biobehavioral factors. While somatosensory function declines are associated with peripheral nervous system degradation, little is known regarding correlates with the central nervous system and brain structure in particular. The objectives of this study were to examine age-related declines in somatosensory function using innocuous and noxious stimuli, across two anatomical testing sites, with considerations for affect and cognitive function, and associations between somatosensory function and brain structure in older adults. Research Design and Methods A cross-sectional analysis included 84 ‘younger’ (n = 22, age range: 19-24 years), and ‘older’ (n = 62, age range: 60-94 years) healthy adults who participated in the Neuromodulatory Examination of Pain and Mobility Across the Lifespan (NEPAL) study. Participants were assessed on measures of somatosensory function (quantitative sensory testing), at two sites (metatarsal and thenar) using standardized procedures, and completed cognitive and psychological function measures, and structural MRI. Results Significant age x test site interaction effects were observed for warmth detection (p=0.018, partial eta 2=0.10) and heat pain thresholds (p=0.014, partial eta 2=0.12). Main age effects were observed for mechanical, vibratory, cold, and warmth detection thresholds (p’s<0.05), with older adults displaying a loss of sensory function. Significant associations between somatosensory function and brain grey matter structure emerged in the right occipital region, the right temporal region, and the left pericallosum. Discussion and Implications Our findings indicate healthy older adults display alterations in sensory responses to innocuous and noxious stimuli compared to younger adults and, furthermore, these alterations are uniquely impacted by anatomical site. These findings suggest a non-uniform decline in somatosensation in older adults, which may represent peripheral and central nervous system alterations part of aging processes.