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Editor’s Perspective What We Already Know about This Topic The nociception level index (Medasense Biometrics Ltd., Ramat Gan, Israel), is a reliable measure of moderate to intense noxious stimulation during anesthesia and surgery What This Article Tells Us That Is New In a randomized trial in patients having major abdominal surgery, compared to standard practice, nociception level-guided analgesia resulted in 30% less intraoperative remifentanil consumption Background The multidimensional index of nociception, the nociception level, outperforms blood pressure and heart rate in detection of nociceptive events during anesthesia. We hypothesized that nociception level–guided analgesia reduces opioid consumption and suboptimal anesthesia events such as low blood pressure and use of vasoactive medication. Methods In this single-blinded randomized study, 80 American Society of Anesthesiologists class I–III adult patients of either sex, scheduled for major abdominal procedures under remifentanil/propofol anesthesia by target-controlled infusion, were included. During the procedure nociception level, noninvasive blood pressure, and heart rate were monitored. Patients were randomized to receive standard clinical care or nociception level–guided analgesia. In the nociception level–guided group, remifentanil concentration was reduced when index values were less than 10 or increased when values were above 25 for at least 1 min, in steps of 0.5 to 1.0 ng/ml. Propofol was titrated to bispectral index values between 45 and 55. The primary outcomes of the study were remifentanil and propofol consumption and inadequate anesthesia events. Results Compared with standard care, remifentanil administration was reduced in nociception level–guided patients from (mean ± SD) 0.119 ± 0.033 to 0.086 ± 0.032 μg · kg-1 · min-1 (mean difference, 0.039 μg · kg-1 · min-1; 95% CI, 0.025–0.052 μg · kg-1 · min-1; P < 0.001). Among nociception level–guided patients, 2 of 40 (5%) experienced a hypotensive event (mean arterial pressure values less than 55 mm Hg) versus 11 of 40 (28%) patients in the control group (relative risk, 0.271; 95% CI, 0.08–0.77; P = 0.006). In the nociception level–guided group, 16 of 40 (40%) patients received vasoactive medication versus 25 of 40 (63%) patients in the standard care group (relative risk, 0.64; 95% CI, 0.40–0.99; P = 0.044). Conclusions Nociception level-guided analgesia during major abdominal surgery resulted in 30% less remifentanil consumption.

In spite of systematic investigations, the existence of a specific cortex that could encode for the intensities of somatosensory stimuli, including within nociceptive ranges, is still a matter of debate. The present consensus is that pain is expressed in a distributed network made of thalamus, SII, insula, ACC, and, less consistently, SI. Here we argument that there must be an entrance to this network. The common denominator to every functional imaging study is that the subjects can distinguish between noxious and non-noxious stimuli, or between two different intensities of noxious stimuli. This is associated with a consistent activation of the insula-SII cortices while activations in other brain areas may be missing or sub-significant. In other words, the operculo-insular cortex activations are the most robust pain-related activations across studies, whatever the manipulation of the pain components, except the discriminative one. Intra-cerebral recordings also pointed out this piece of cortex as being able to encode for pain intensity. As a last physiological argument, stimulating directly the brain with small intensities standardized electrical shocks elicited pain sensations selectively if the electrode was in the operculo-insular cortex. Human models of disease confirmed that epileptic discharges in the insular cortex can produce ictal pain. Insular epilepsy (or propagation of discharges to the insular cortex) is the only focal epilepsy to be possibly associated with painful symptoms. Finally, unique and focal lesions of the posterior operculo-insular cortices were able to remove (or at least to impair) thermosensory and nociceptive functions. Thus, the operculo-insular area can be presented as the only area in the brain to respond to the features of a primary thermosensory and nociceptive cortex. This area is likely to be the starting point of the nociceptive-related networks. Future investigations are necessary to determine how this "pain symphony" between these different brain areas is temporally orchestrated. Developments of new targets for functional neurosurgery could benefit of such localized and initiating processes, for instance focal neurostimulations.

Environmental enrichment (EE) can alter anxiety as well as perception of nociceptive stimuli, suggesting a relationship between well-being and analgesia. Considering that, we aimed to evaluate the influence of different EE types on anxiety and peripheral pain sensitivity of male Wistar rats. Animals were submitted to two different types of EE: On the first one, animals were housed in standard size cages after weaning and received three different objects, one type per week, on a regular basis (simple EE - sEE). On the second one, animals were born in an already enriched environment and, after five weeks, were housed in larger cages and received five different objects, three of each type per week, on a regular basis (improved EE - iEE). Control group remained in standard cages and did not receive objects. Within 7 weeks of life, anxiety and thermal sensibility were evaluated using elevated plus maze and tail flick tests, respectively. Mechanical hyperalgesia was analyzed in the presence of acute and chronic noxious stimuli by paw pressure test. Both EE protocols tested were effective in diminish anxiety but they did not alter thermal sensibility. On the other hand, sEE protocol did not alter acute and chronic induced mechanical hypersensitivity, whereas iEE completely abolished such pain behavior, even without exercise wheel as part of the enrichment. Our results show that specific parameters (anxiety and pain sensitivity) can be differentially modulated depending on EE protocol used, making possible the implementation of welfare to experimental animals in pain research.

Prominent 7–12 Hz oscillations in frontal cortical networks in rats have been reported. However, the mechanism of generation and the physiological function of this brain rhythm have not yet been clarified. Multichannel extracellular field potentials of the ACC were recorded and analyzed using the current source density method in halothane-anesthetized rats. Spontaneous high-current spikes (HCSs) were localized in the deep part of layer II/III and upper part of layer V of the ACC. The frequency of HCSs in the ACC was 7–12 Hz, with an amplitude of 6.5 ± 0.76 mV/mm(2) and duration of 55.24 ± 2.43 ms. The power density significantly decreased (84.56 ± 6.93%, p < 0.05, t test) after pinching the hindpaw and significantly increased (149.28 ± 15.96%) after treatment with morphine. The suppressive effect of pinching was reversed by naloxone (0.7 mg/kg, i.p.). HCSs coincided with initiation of the depolarization of cingulate neurons and remained in a depolarized upstate. The occurrence of cingulate HCSs was persistently preceded by a hyperpolarization phase and a burst of multiunit spike activity in the medial dorsal thalamic nucleus. Spontaneous field-potential oscillations changed from 10 Hz to a lower band (i.e., ∼7.5 Hz) when a central poststroke pain condition was induced. The central poststroke pain group had a higher average coherence coefficient compared with the control group. Our results indicate that spontaneous cingulate cortical HCSs could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms in physiological and pathological pain states. SIGNIFICANCE STATEMENT This study elucidated the mechanism of generation and physiological function of prominent 7–12 Hz frequency oscillations in frontal cortical networks in rats. Spontaneous cingulate cortical high-current spikes in anesthetized rats could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms. Suppression of the anterior cingulate cortex-filtered EEG during noxious stimulation may have resulted from the desynchronization of high-current spikes in the ACC. The enhancement of fast Fourier transform power after a systemic morphine injection suggested that the opioid system may play an important role in synchronizing cingulate cortical neuronal networks. Spontaneous cingulate high-current spikes may also play an important role in thalamocortical dysrhythmia in central poststroke pain.

Pain consists of sensory-discriminative and negative-emotional components. The negative-emotional component of pain is closely related to aversive motivation that promotes avoidance behaviors to escape from noxious stimuli and aversive learning to avoid the cue (conditioned stimulus) associated with noxious stimulation. Recent behavioral studies have revealed the brain regions that mediate the negative-emotional component of pain, including the anterior cingulate cortex, amygdala, and bed nucleus of the stria terminalis (BNST). This review outlines the roles of peptidergic, glutamatergic and noradrenergic transmissions within the BNST in the negative-emotional component of pain and discusses the function of BNST neurons in the regulation of ventral tegmental area dopaminergic neurons, which have important roles in aversive and appetitive motivational systems.

Complexity in movement planning, arising from diverse temporal and spatial sources, places a computational burden on the central nervous system. However, the efficacy with which humans can perform natural, highly trained movements suggests that they have evolved effective behavioral strategies that simplify the computational burden. The specific aim of our research was to use three-dimensional high-speed video to determine whether the tail nociceptive withdrawal response (NWR) to noxious heat stimuli delivered at locations that varied both circumferentially and rostral-caudally on the tail depended on the location of the stimulus in spinalized rats. In particular, we sought to determine whether the movement strategy was categorical (limited number of directions) or continuous (any variation in stimulus location results in a variation in response direction). In spinalized rats, localized, noxious heat stimuli were delivered at eight locations circumferentially around the tail and at five rostral-caudal levels. Our results demonstrate that at all rostral-caudal levels, response movement direction was bimodal regardless of circumferential stimulus location-either ~ 64° left or right of ventral. However, in spite of tight clustering, movement direction varied significantly but weakly according to circumferential location, in that responses to stimuli were more lateral for lateral stimulus locations. In contrast, changes in stimulus level strongly affected movement direction, in that a localized bend response closely matched the level of the stimulus. Together, our results demonstrate, based on movement analysis in spinalized rats, that the NWR employs a hybrid categorical-continuous strategy that may minimize the harmful consequences of noxious stimuli.

Noxious stimuli induce a nociceptive withdrawal reflex (NWR) to protect the tissue from injury. Although the NWR was once considered as a stereotyped response, previous studies report distinct responses depending on the stimulation site and context for limbs. We aimed to determine whether noxious stimuli over the trunk produced adaptable complex NWR. We hypothesized that organization of the NWR of the trunk muscle would vary with the site of noxious input and would differ between body and spine postures, which modify the potential for specific muscles to remove threat. Fourteen participants were tested in sitting and three lumbar spine postures in side lying (neutral, flexion and extension). Noxious electrical stimuli were applied over the sacrum, spinous process of L3 and T12, lateral side of the 8th rib and anterior midline. NWR latency and amplitude were recorded with surface electromyography (EMG) electrodes over different trunk muscles. Distinct patterns of muscle activation depended on the stimulation site and were consistent with motor strategies needed to withdraw from the noxious stimuli. The NWR pattern differed between body positions, with less modulation observed in sitting than side lying. Spine posture did not affect the NWR organisation. Our results suggest the circuits controlling trunk muscle NWR presents with adaptability as a function of stimulation site and body position by utilizing the great complexity of the trunk muscle system to produce an efficient protective response. This suggests that the central nervous system (CNS) uses multiple adaptable strategies that are unique depending on which context the noxious stimuli are applied.

Supplemental Digital Content is Available in the Text. Our work reveals that the platelet-derived growth factor-BB, by inhibiting nociceptive M-type potassium channels, acts as a pain-inducing proinflammatory factor that significantly contributes to inflammatory pain., Endogenous inflammatory mediators contribute to the pathogenesis of pain by acting on nociceptors, specialized sensory neurons that detect noxious stimuli. Here, we describe a new factor mediating inflammatory pain. We show that platelet-derived growth factor (PDGF)-BB applied in vitro causes repetitive firing of dissociated nociceptor-like rat dorsal root ganglion neurons and decreased their threshold for action potential generation. Injection of PDGF-BB into the paw produced nocifensive behavior in rats and led to thermal and mechanical pain hypersensitivity. We further detailed the biophysical mechanisms of these PDGF-BB effects and show that PDGF receptor–induced inhibition of nociceptive M-current underlies PDGF-BB–mediated nociceptive hyperexcitability. Moreover, in vivo sequestration of PDGF or inhibition of the PDGF receptor attenuates acute formalin-induced inflammatory pain. Our discovery of a new pain-facilitating proinflammatory mediator, which by inhibiting M-current activates nociceptive neurons and thus contributes to inflammatory pain, improves our understanding of inflammatory pain pathophysiology and may have important clinical implications for pain treatment.

Nociceptors, sensory neurons that detect damage or potential damage to the body, are the first stage of communicating noxious stimuli from the periphery to central nervous system (CNS). In this study, long-term potentiation (LTP) in the CNS of the medicinal leech, Hirudo verbana, was examined, taking advantage of the ability to selectively record from nociceptive synapses in this model organism. High frequency stimulation (HFS) of nociceptors produced a persistent increase in synaptic transmission and this LTP was both NMDA receptor-mediated and synapse-specific. Surprisingly, inhibition of NMDA receptors during HFS “uncovered” a persistent form of depression. This long-term depression (LTD) was mediated by the endocannabinoid 2-arachidonoyl glycerol (2-AG) acting on a TRPV (transient receptor potential vanilloid) –like channel. These observations suggest that (1) NMDA receptor mediated LTP is observed in nociceptors across both vertebrate and invertebrate phyla and (2) there may be an interaction between NMDA receptor-mediated and endocannabinoid-mediated forms of synaptic plasticity in nociceptors. Specifically, the NMDA receptor mediated processes may suppress endocannabinoid signaling. Such findings could be significant for understanding cellular mechanisms behind nociceptive sensitization and perhaps their contribution to chronic pain.

Pain is the leading cause for hospitalization in patients with sickle cell disease (SCD). While the characteristics of SCD pain can vary widely between patients and between phases of the disease (e.g. vasoocclusive crisis pain vs. chronic pain), similar neuronal mechanisms likely underlie the various aspects of nociceptive processing. In the peripheral nervous system, small unmyelinated C fibers and lightly-myelinated Aδ fibers detect and transmit noxious stimuli. Both classes of neurons express members of the transient receptor potential (TRP) family, a group of ligand gated ion-channels that are activated by thermal, chemical, and mechanical stimuli. Promiscuous TRP channel family members are activated by a wide range of stimuli, many of which are dysregulated in patients with SCD and transgenic SCD mouse models. In 2011, our lab published the first report of TRP channel contributions to rodent SCD pain. Since that time, additional basic and clinical research efforts have investigated the genetic and biochemical status of TRP channels in SCD, placing particular focus on TRPV1. This review will discuss these advances and highlight the clinical SCD presentations that have not yet been studied, but which may be mediated by TRP channel activity.

Objectives The hypoalgesic effects of exercise are well described, but there are conflicting findings for different modalities of pain; in particular for mechanical vs thermal noxious stimuli, which are the most commonly used in studies of exercise-induced hypoalgesia. The aims of this study were 1) to investigate the effect of aerobic exercise on pressure and heat pain thresholds that were well equated with regard to their temporal and spatial profile and 2) to identify whether changes in the excitability of nociceptive pathways—measured using laser-evoked potentials—accompany exercise-induced hypoalgesia. Subjects Sixteen healthy adults recruited from the University of New South Wales. Methods Pressure and heat pain thresholds and pain ratings to laser stimulation and laser-evoked potentials were measured before and after aerobic cycling exercise and an equivalent period of light activity. Results Pressure pain thresholds increased substantially after exercise (rectus femoris: 29.6%, d = 0.82, P 0.06). Conclusions This is the first investigation to compare the effects of exercise on pressure and heat pain using the same stimulation site and pattern. The results show that aerobic exercise reduces mechanical pain sensitivity more than thermal pain sensitivity.

Inhibitory pain modulation has been reported to be deficient in adults across different types of chronic pain, including migraine. To determine whether a similar phenomenon occurs in youth, we performed a quantitative sensory testing investigation in adolescents with migraine (N = 19). These patients were compared to healthy adolescents with (Fam-His; N = 20) or without (Healthy; N = 29) a family history of migraine (eg, first-degree relative with migraine). Subjects were first familiarized with the stimuli and visual analogue rating scales using graded noxious stimuli (0°C, 43-49°C range). These data were used to explore potential pain sensitivity differences between the groups. Pain inhibition was assessed by conditioned pain modulation (CPM), which used both suprathreshold heat pain (heat CPM) and pressure pain thresholds (pressure CPM) as the test stimuli before and during cold-water immersion (8°C). In response to the graded heat stimuli, Fam-His participants reported higher pain intensity ratings compared with patients with migraine, who in turn reported higher pain intensity ratings than the healthy controls (F = 3.6, [df = 2, 459], P = 0.027). For heat and pressure CPM, there was no significant group difference in the magnitude of CPM responses. Thus, adolescents with migraine and healthy adolescents have similar inhibitory pain modulation capability, despite having marked differences in pain sensitivity. Although Fam-His participants are asymptomatic, they demonstrate alterations in pain processing, which may serve as markers for prediction of migraine development.

Objectives Damage to the posterior cerebellum can cause affective deficits in patients. In adults, cerebellar infarcts result in thermal hyperalgesia and affect descending modulation of pain. This study evaluated the effect of resection of low‐grade cerebellar tumors on pain processing in human children. Methods Twelve pediatric patients treated with surgery only for low‐grade gliomas (8 females, 4 males; mean age = 13.8 ± 5.6) and twelve matched controls (8 females, 4 males; mean age = 13.8 ± 5.7) were evaluated using quantitative sensory testing and fMRI. Five patients had tumors localized to posterior cerebellar hemispheres, henceforth identified as Crus Patients. Results Crus Patients had significantly lower pain tolerance to a cold pressor test than controls. No significant differences were detected between subject groups for heat and cold detection thresholds (HDT, CDT), and heat and cold pain thresholds (HPT, CPT). Crus Patients also showed significantly decreased fMRI responses to painful heat in anterior insula, which has been associated with pain affect. Interpretation Damage to posterior cerebellar hemispheres disrupted affective pain processing and endogenous pain modulation, resulting in decreased pain tolerance to suprathreshold noxious stimuli. This suggests that surgical resection of this region in children may increase the risk of developing pain disorders.

Background Objective monitoring of pain during and after surgery has been elusive. Recently, Analgesia Nociception Index (ANI) monitor based on the high frequency component of heart rate variability has been launched into clinical practice. We monitored analgesia during craniotomy using ANI monitor and compared it with cardiovascular parameters and response entropy (RE) of entropy monitor. Materials and methods In 21 patients undergoing a craniotomy for a supratentorial lesion, we monitored ANI, heart rate (HR), mean arterial pressure (MAP), state entropy, and RE throughout the surgery. Also, ANI, hemodynamic variables and spectral entropy values were noted at the times of maximal stimulation, such as induction, intubation, head pin fixation, skin incision, craniotomy, durotomy, and skin closure. We also compared ANI with RE during administration of bolus doses of fentanyl. Results There was an inverse correlation between ANI values and the hemodynamic changes. When the HR and MAP increased, ANI decreased suggesting a good correlation between hemodynamics and ANI values during the times of maximal stimulation. State entropy and RE did not change significantly in response to bolus doses of fentanyl administered during the course of surgery, while ANI increased significantly. Conclusion In neurosurgical patients undergoing elective supratentorial craniotomy, ANI measures response to noxious stimuli with at least as much reliability as hemodynamic variables and changes in ANI parallel the changes in HR and MAP. ANI is superior to RE for measurement of response to noxious stimuli.

Background Both protective and therapeutic functions of insulin-like growth factor-1 (IGF-1) in brain injury have been reported, but its effects on cognitive sequelae after septic encephalopathy (SE) remain unclear. Materials and methods This study was divided into three parts, and a septic model was built by cecal ligation and puncture (CLP). First, survival analysis was performed, and IGF-1’s effects on long-term cognition and depressive emotion were assessed. Second, the characteristics of IGF-1 function in cognition were evaluated. Finally, cytochrome C, caspase-9, tumor necrosis factor receptor (TNFR), and caspase-8 levels as well as cell apoptosis in the hippocampus were evaluated. Results IGF-1 did not reduce mortality or alleviate depressive symptoms in septic rats, but improved the memory of noxious stimulation and spatial learning and memory. These effects were observed only when IGF-1 was administered within 0–6 hours after CLP. Moreover, cytochrome C and caspase-9 expression levels were increased at 6 hours after CLP in the hippocampus, while TNFR and caspase-8 amounts were not increased until 12 hours after CLP. Cell apoptosis increased at 12 hours after CLP, but was inhibited by IGF-1. Conclusion Cognitive impairment in rats recovering from SE is associated with cell apoptosis in the hippocampus. Supplementation of IGF-1 reduces cell apoptosis by preventing the over-expression of cytochrome C and TNFR, and results in improved cognitive function. However, improvement only occurs when IGF-1 is administered at the early stage (within 6 hours) of sepsis. As cytochrome C activation occurs earlier than that of TNFR in this study, cytochrome C may be the main factor inducing apoptosis in early SE.

In humans, spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma) that can engage pain (nociceptive) fibers. Prior work has shown that this nociceptive input can expand the area of tissue damage (secondary injury), undermine behavioral recovery, and enhance the development of chronic pain. Here, it is shown that nociceptive input given a day after a lower thoracic contusion injury in rats enhances the infiltration of red blood cells at the site of injury, producing an area of hemorrhage that expands secondary injury. Peripheral nociceptive fibers were engaged 24 h after injury by means of electrical stimulation (shock) applied at an intensity that engages unmyelinated pain (C) fibers or through the application of the irritant capsaicin. Convergent western immunoblot and cyanmethemoglobin colorimetric assays showed that both forms of stimulation increased the concentration of hemoglobin at the site of injury, with a robust effect observed 3–24 h after stimulation. Histopathology confirmed that shock treatment increased the area of hemorrhage and the infiltration of red blood cells. SCI can lead to hemorrhage by engaging the sulfonylurea receptor 1 (SUR1) transient receptor potential melastatin 4 (TRPM4) channel complex in neurovascular endothelial cells, which leads to cell death and capillary fragmentation. Histopathology confirmed that areas of hemorrhage showed capillary fragmentation. Co-immunoprecipitation of the SUR1-TRPM4 complex showed that it was up-regulated by noxious stimulation. Shock-induced hemorrhage was associated with an acute disruption in locomotor performance. These results imply that noxious stimulation impairs long-term recovery because it amplifies the breakdown of the blood spinal cord barrier (BSCB) and the infiltration of red blood cells, which expands the area of secondary injury.

Background: Noxious stimulation such as skull pin insertion for craniotomy elicits a significant hemodynamic response. Both regional analgesic techniques (pin-site infiltration [PSI] and scalp block [SB]), and systemic strategies (opioids, alpha-2 agonists, anesthetics, and beta-blockers) have shown to attenuate this response. Analgesia Nociception Index (ANI) provides objective information about the magnitude of nociception and adequacy of analgesia. This study compared ANI and hemodynamic changes in patients receiving local anesthetic SB versus PSI during skull pin application for craniotomy. Materials and Methods: Sixty adult patients scheduled for elective supratentorial tumor surgery were randomly allocated to receive local anesthetic SB or PSI for skull pin insertion after the induction of anesthesia. Data regarding heart rate (HR), blood pressure (BP), and ANI were collected every minute for 5 min after the skull pin insertion beginning from the baseline. Results: A significant difference was observed in ANI values between the SB (higher ANI) and the PSI groups during skull pin insertion, P < 0.001 and P = 0.003 for ANIi and ANIm, respectively. Similarly, a significant difference was seen in HR and BP both within and between the two groups during skull pin insertion (P < 0.001 for both). The magnitude and duration of change were smaller in the SB group compared with the PSI group for the parameters studied. A strong negative linear correlation was noted between ANI and hemodynamic parameters. Conclusions: The changes in HR, BP, and ANI were significantly less with local anesthetic SB compared with PSI during skull pin insertion in patients undergoing supratentorial craniotomy.

Classic anatomical atlases depict a contralateral hemispheral representation of each side of the face. Recently, however, a bilateral projection of each hemiface was hypothesized, based on animal studies that showed the coexistence of an additional trigeminothalamic tract sprouting from the trigeminal principal sensory nucleus that ascends ipsilaterally. This study aims to provide an anatomical substrate for the hypothesized bilateral projection. Three post-mortem human brainstems were scanned for anatomical and diffusion magnetic resonance imaging at 11.7T. The trigeminal tracts were delineated in each brainstem using track density imaging (TDI) and tractography. To evaluate the reconstructed tracts, the same brainstems were sectioned for polarized light imaging (PLI). Anatomical 11.7T MRI shows a dispersion of the trigeminal tract (tt) into a ventral and dorsal portion. This bifurcation was also seen on the TDI maps, tractography results and PLI images of all three specimens. Referring to a similar anatomic feature in primate brains, the dorsal and ventral tracts were named the dorsal and ventral trigeminothalamic tract (dtt and vtt), respectively. This study shows that both the dtt and vtt are present in humans, indicating that each hemiface has a bilateral projection, although the functional relevance of these tracts cannot be determined by the present anatomical study. If both tracts convey noxious stimuli, this could open up new insights into and treatments for orofacial pain in patients.

Irritable bowel syndrome (IBS) is a relatively common condition characterized by abdominal pain, among other symptoms, that significantly impacts the quality of life of IBS patients. Therapeutic treatment of IBS results in limited success, and the focus is placed on relieving patients of some of the symptoms, visceral pain in particular. Acupuncture is commonly used as a treatment modality of choice. However, the debate on whether acupuncture can be effectively used for this purpose is ongoing. In this work, we critically review the available literature to establish a potential mechanism of action in treating visceral pain in IBS using acupuncture. The sources used are Google Scholar, EBSCO, Cochrane Library and PubMed as well as Chinese database sources. The keywords used in the literature search are “acupuncture,” “IBS,” “Irritable Bowel Syndrome,” and “visceral pain.” We find that the literature strongly indicates that acupuncture, by stimulating points located on the dermatomes proximal to the spinal level of the area where the sympathetic outflow of the particular gut area affected by the pain is, can interfere with the efferent signal that transports information about the noxious stimuli and interrupt the “connectivity” between the gut and brain, and as a final result, reduce or stop IBS pain. Our findings justify that clinical trials are conducted to test the utility of acupuncture in treating abdominal visceral pain in IBS.

Tramadol has been demonstrated to provide analgesia in rats and mice and has been increasingly used in other small companion mammals for treatment of moderate to severe pain. Currently no evidence is available that supports the use of tramadol as an effective analgesic in chinchillas. The purpose of this study was to evaluate the antinociceptive efficacy and safety of subcutaneously administered tramadol in chinchillas. Initial dose-escalation studies were performed to determine if dose-dependent adverse effects occur in chinchillas. At 60 mg/kg subcutaneously (SC), but not at lower doses, tramadol induced clinically significant dose-limiting adverse effects, consisting of whole body tremors and facial muscle fasciculation. Therefore, in a subsequent analgesimetry experiment, tramadol was evaluated at a single dose of 10, 20, and 40 mg/kg SC in a randomized, blinded, controlled, complete crossover design. Thermal antinociceptive efficacy was determined by measuring hindlimb withdrawal latencies following a thermal noxious stimulus (Hargreaves’ method) at 0, 1, 2, 4, and 8 hours after drug administration. Changes in daily food intake and fecal output following tramadol administration were measured. At 10 to 40 mg/kg SC no thermal antinociceptive effects could be demonstrated. A self-limiting and transient significant reduction in food intake and fecal output occurred in a dose-dependent manner when tramadol was administered at 20 and 40 mg/kg. Based on the results of this study tramadol cannot be recommended as an analgesic drug in chinchillas.

Two similar proteolytic cascades lead to release of bradykinin and lysbradykinin in tissues; these peptides act as autocoids, the first favouring blood clotting and endothelial protection, the second by initiating and maintaining tissue reactions to noxious stimuli. Kinin biological actions are mediated by two different receptor types, the constitutive B2 which promotes initial reactions and the inducible B1 which may later maintain mechanisms of defence and repair. Keywords: kallikreins; kinins; B1 and B2 receptors

Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one's hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response-such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1Cre and LBX1Flpo drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that-in humans-produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei1-3. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.

The present study was undertaken to characterize the behavioral manifestations of nociception and the local mechanisms involved with the nociceptive response elicited by Latrodectus curacaviensis venom (LCV) in mice. After the intraplantar LCV inoculation, spontaneous nociception, mechanical and thermal nociceptive thresholds, motor performance, edema and cytokine levels were evaluated using von Frey filaments, hot/cold plate, rota-rod, plethismometer and ELISA, respectively. Analysis of LCV was performed by SDS-PAGE and chromatography. Intraplantar injection of LCV (1–100 ng/paw) induced intense and heat-sensitive spontaneous nociception, mediated by serotonin and bradykinin receptors, TRPV1 channels, as well as by transient local inflammation. LCV (0.1–10 ng/paw) induced mechanical allodynia, which was reduced by the local pretreatment with H1 receptor or TRPV1 antagonists. Corroborating the TRPV1 involvement, in thermal nociception assays, LCV induced a similar response to that of capsaicin, a TRPV1 agonist, facilitating the response to noxious hot stimuli and inhibiting the response to cold noxious stimulation. LCV promoted mast cell degranulation, increased IL-1β paw levels, but did not produce a relevant edematogenic effect. Analysis of LCV components showed a predominance of high molecular weight proteins. This work provides the first mechanistic hypothesis to explain the local pain induced by LCV, the most frequent clinical symptom of human envenomation.

Medetomidine and isoflurane are commonly used for general anaesthesia in fMRI studies, but they alter cerebral blood flow (CBF) regulation and neurovascular coupling (NVC). In addition, medetomidine induces hypoinsulinemia and hyperglycaemia, which also alter CBF regulation and NVC. Furthermore, sudden changes in arterial pressure induced by noxious stimulation may affect NVC differently under medetomidine and isoflurane anaesthesia, considering their different effects on vascular functions. The first objective of this study was to compare NVC under medetomidine and isoflurane anaesthesia during noxious stimulation. The second objective was to examine whether fasting may improve NVC by reducing medetomidine-induced hyperglycaemia. In male Wister rats, noxious electrical stimulation was applied to the sciatic nerve in fasted or non-fasted animals. CBF and local field potentials (LFP) were recorded in the somatosensory cortex to assess NVC (CBF/LFP ratio). The CBF/LFP ratio was increased by medetomidine compared with isoflurane (p = 0.004), but this effect was abolished by fasting (p = 0.8). Accordingly, medetomidine produced a threefold increase in blood glucose (p < 0.001), but this effect was also abolished by fasting (p = 0.3). This indicates that isoflurane and medetomidine anaesthesia alter NVC differently, but the undesirable glucose dependent effects of medetomidine on NVC can be prevented by fasting.

Inflammation modifies the input-output properties of peripheral nociceptive neurons, thus leading to hyperalgesia, a condition in which the perception of noxious heat stimuli is altered such that the same stimulus produces enhanced pain. The increased nociceptive output enters the superficial dorsal spinal cord (SDH), which comprises the first CNS network integrating the noxious information. Here we used in vivo calcium imaging and a computational approach to investigate how the SDH network in mice encodes the injury-mediated abnormal input from peripheral nociceptive neurons. We show that the application of noxious heat stimuli to the hind paw in naïve mice before induction of injury affects the activity of 70% of recorded neurons by either increasing or suppressing it. Application of the same noxious heat stimuli to hyperalgesic skin following injury leads to activation of previously non-responded cells and de-suppression of the “suppressed” neurons. We further demonstrate that reduction in synaptic inhibition mimics the response to the noxious stimuli in hyperalgesic conditions. Using a computational model of the SDH network, we predict that the “disinhibitory” effect of hyperalgesic stimuli results from the inflammation-mediated increased afferent input to the SDH network and a decrease in SDH inhibition. Both of these processes synergistically contribute to the injury-mediated increase in SDH output towards higher brain centers.

Adolescence is a sensitive period for both brain development and the emergence of chronic pain particularly in females. However, the brain mechanisms supporting pain perception during adolescence remain unclear. This study compares perceptual and brain responses to pain in female adolescents and adults to characterize pain processing in the developing brain. Thirty adolescent (ages 13-17) and thirty adult (ages 35-55) females underwent a functional MRI scan involving acute experimental pain. Participants received 12 ten-second noxious pressure stimuli which were applied to the left thumbnail at 2.5 and 4 kg/cm2, and rated pain intensity and unpleasantness on a visual analogue scale. We found a significant group-by-stimulus intensity interaction on pain ratings. Compared to adults, adolescents reported greater pain intensity and unpleasantness in response to 2.5 kg/cm2, but not 4 kg/cm2. Adolescents showed greater medial-lateral prefrontal cortex (PFC) and supramarginal gyrus activation in response to 2.5 kg/cm2, and greater medial PFC and rostral anterior cingulate responses to 4 kg/cm2. Adolescents showed augmented pain-evoked responses in the Neurologic Pain Signature and greater activation in the default mode (DMN) and ventral attention (VAN) networks. Also, the amygdala and associated regions played a stronger role in predicting pain intensity in adolescents, and activity in DMN and VAN regions more strongly mediated the relationship between stimulus intensity and pain ratings. This study provides the first evidence of augmented pain-evoked brain responses in healthy female adolescents involving regions important for nociceptive, affective and cognitive processing, in line with their augmented sensitivity to low-intensity noxious stimuli.

Introduction A major goal in neonatal medicine is to reduce stress as much as possible in routine care. Bathing is one of the important routine cares for neonates, but it makes a big environmental change for them. We aimed to examine whether water temperature, room temperature, and position changes in tub bathing serve as noxious stimuli to neonates. Methods This prospective trial was performed in full-term and non-low-birth-weight neonates admitted to the hospital between July 2020 and March 2021. Those with underlying diseases, fetal distress, infection, and other medical conditions were excluded. Measurements were taken during the neonates’ first tub bath since birth, which was performed by a trained nurse. Changes in regional oxygen saturation (rSO2), determined using near-infrared spectroscopy, and water and room temperature, were examined at five different time points: upon entering the bath, head washing, position change, exiting the bath, and during the 3 min after bathing. Results In total, 17 neonates were analyzed. No changes in rSO2 due to head washing or position change were observed; however, rSO2 significantly decreased upon entering (78.5 ± 4.1% vs. 75.7 ± 4.1%, p

Astrocytes are critical regulators of neuronal function in the central nervous system (CNS). We have previously shown that astrocytes in the spinal dorsal horn (SDH) have increased intracellular Ca2+ levels following intraplantar injection of the noxious irritant, formalin. However, the underlying mechanisms remain unknown. We investigated these mechanisms by focusing on the role of descending noradrenergic (NAergic) signaling because our recent study revealed the essential role of the astrocytic Ca2+ responses evoked by intraplantar capsaicin. Using in vivo SDH imaging, we found that the Ca2+ level increase in SDH astrocytes induced by intraplantar formalin injection was suppressed by ablation of SDH-projecting locus coeruleus (LC)-NAergic neurons. Furthermore, the formalin-induced Ca2+ response was dramatically decreased by the loss of α1A-adrenaline receptors (ARs) in astrocytes located in the superficial laminae of the SDH. Moreover, similar inhibition was observed in mice pretreated intrathecally with an α1A-AR-specific antagonist. Therefore, activation of α1A-ARs via descending LC-NAergic signals may be a common mechanism underlying astrocytic Ca2+ responses in the SDH evoked by noxious stimuli, including chemical irritants.

BACKGROUND Visual deprivation leads to behavioural adaptations. Early visual deprivation has greater effects on sensory systems compared with late visual deprivation. Although this has been well studied, the impact of visual deprivation on pain sensitivity has scarcely been investigated. In humans, one study indicates that pain sensitivity is increased in early, but not late-onset blindness. In animals, one study indicates that sensitivity to noxious stimulation is increased in anophthalmic mice, but the impact of late visual deprivation on sensitivity remains unknown. The aim of this behavioural study was to examine sensitivity to noxious stimulation in mice with early and late visual deprivation. We hypothesized that visual deprivation would have different effects on sensitivity to noxious stimulation depending on its onset. METHODS In Experiment 1, mechanical and thermal sensitivity was examined in four ZRDBA mouse groups: sighted mice, anophthalmic mice, dark-reared sighted mice and adult sighted mice deprived of vision for one week. In Experiment 2, mechanical and thermal sensitivity was examined in adult sighted ZRDBA mice deprived of vision for two months. RESULTS Anophthalmic and dark-reared mice showed mechanical and thermal hypersensitivity, while the one-week visual deprivation did not alter sensitivity. The two-month deprivation also resulted in mechanical and thermal hypersensitivity. CONCLUSIONS These results indicate that early visual deprivation, regardless of the integrity of the visual system, induces hypersensitivity. Moreover, the present findings indicate that late visual deprivation may induce mechanical and thermal hypersensitivity, although this depends on visual deprivation duration. These results have implications for the biological significance of pain in the blind. SIGNIFICANCE Sensory deprivation induces behavioural adaptions. For most sensory systems, the extent of these adaptations generally depends on the stage of cerebral development. In contrast, the present results indicate that for the nociceptive system, both early and late visual deprivation have similar effects. Anophthalmic, dark-reared mice and adult mice deprived of vision for two months showed thermal and mechanical hypersensitivity. This shows a clear interaction between visual and nociceptive systems and has implications for the biological significance of pain in the blind.

SummaryPain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) – rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans we used simultaneous whole brain-spinal cord pharmacological-fMRI (N=39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH, C6 segment) whose activity mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC recruits PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-DH and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation is mediated by opioidergic ACC-PAG-RVM descending control which supresses spinal nociceptive activity.

Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.

The two-point discrimination threshold (2PDT) has been used to investigate the integration of sensory information, especially in relation to spatial acuity. The 2PDT has been investigated for both innocuous mechanical stimuli and noxious thermal stimuli; however, previous studies used different stimulation modalities to compare innocuous and noxious stimuli. This study investigated the 2PDT in 19 healthy participants, using both thermal (laser) and mechanical stimulation modalities. Within each modality, both innocuous and noxious intensities were applied. Concurrent point stimuli were applied to the right volar forearm, with separation distances of 0-120 mm, in steps of 10 mm. 0 mm corresponds to a single point. Following each stimulus, the participants indicated the number of perceived points (1 or 2) and the perceived intensity (NRS: 0: no perception, 3: pain threshold, 10: maximum pain). The order of stimulation modality, intensity and distance was randomized. The 2PDT for innocuous and noxious mechanical stimuli was 34.7 mm and 47.1 mm, respectively. For thermal stimuli, the 2PDT was 80.5 mm for innocuous stimuli and 66.9 mm for noxious stimuli. The average NRS for thermal stimuli was 1.6 for innocuous intensities and 4.0 for noxious intensities, while for mechanical stimuli, the average NRS was 0.9 for innocuous intensities and 3.6 for noxious intensities. This study showed that the 2PDT highly depends on both stimulation modality and intensity. Within each modality, noxious intensities modulates the 2PDT differently, i.e., noxious intensities lowers the 2PDT for thermal stimuli, but increases the 2PDT for mechanical stimuli.

Objective: \ud Altered balance in nociception in response to noxious stimuli is commonly reported in chronic low back pain (LBP). However, it is unclear whether an improvement in the clinical presentation is contingent on a reduction in pain sensitivity. This study investigated whether the quantitative sensory testing (QST) profile changes in people undergoing rehabilitation for LBP. \ud Design: \ud A prospective, observational case-control study. Methods: Forty males and females, 18-40 years' old, (20 with LBP) participated in two sessions. QST was performed at baseline and after discharge from rehabilitation (LBP) or after 3-8 weeks (controls). The QST battery consisted of determining pressure-pain thresholds (PPT) at the low back and shoulder, temporal summation of pain and conditioned pain modulation. Questionnaire data was used to determine pain (Numeric Rating Scale; NRS), disability (Roland-Morris Questionnaire, RMQ), Fear Avoidance Beliefs (FABQ) and The Örebro Musculoskeletal Pain Screening Questionnaire (ÖMPSQ) at baseline and discharge. The treatment effect was determined by calculating the Cohen's d. \ud Results: \ud No significant group x time interactions or main factor effect was found for any of the QST measures. The LBP group reported a significant reduction in NRS (P

Purpose of review Despite the wide prevalence of gastro-esophageal reflux disease (GERD), the neurophysiological mechanisms underlying heartburn perception in the esophagus of patients with GERD remains incompletely understood. Recent studies have highlighted the potential influence sensory afferent nerves innervating the oesophageal epithelium may have on heartburn pathogenesis. The purpose of this review is to consider the current understanding of esophageal afferent neuronal innervation, including the nociceptive role of acid-sensing receptors expressed on these sensory nerves, in relation to pain perception in the esophagus of GERD patients. Recent findings Central and peripheral pathways of sensitization following noxious stimulation of nociceptive receptors expressed on afferent nerves can regulate the strength of sensory nerve activation in the esophagus, which can result in the amplification or suppression of afferent signal transmission. The localization and characterization of mucosal sensory afferent nerves vary between GERD phenotypes and may explain the heterogeneity of symptom perception in patients with apparently similar levels of reflux. Summary In this review, we discuss the relevance of afferent esophageal innervation in heartburn perception, with a particular focus on the pathways of reflux-induced activation of nociceptive nerves.

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.

I review studies that examined the possibility of pain experience in fish and note how they provided guidance on general methods that could be applied to other animals such as decapod crustaceans. The fish studies initially reported the occurrence of prolonged rocking movements in trout and rubbing of their lips if they were injected with acetic acid. Subsequent studies examined the role of morphine in reducing these activities and examined shifts in attention when responding to noxious stimuli. Various studies take up these themes in decapods. The results reported for the two taxonomic groups are remarkably similar and indicate that responses of both go beyond those expected of mere nociceptive reflex. Thus, the idea of pain cannot be dismissed by the argument that fish and decapods respond only by reflex. The responses of both clearly involve central processing, and pain experience, although not proven for either, is a distinct possibility. These studies have been the subjects of highly critical opinion pieces and these are examined and rebutted. The conclusion is that both fish and decapods should be awarded consideration for their welfare.

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.

Although conditioned pain modulation (CPM) is considered to represent descending pain inhibitory mechanisms triggered by noxious stimuli applied to a remote area, there have been no previous studies comparing CPM between pain and tactile systems. In this study, we compared CPM between the two systems objectively using blink reflexes. Intra-epidermal electrical stimulation (IES) and transcutaneous electrical stimulation (TS) were applied to the right skin area over the supraorbital foramen to evoke a nociceptive or a non-nociceptive blink reflex, respectively, in 15 healthy males. In the test session, IES or TS were applied six times and subjects reported the intensity of each stimulus on a numerical rating scale (NRS). Blink reflexes were measured using electromyography (R2). The first and second sessions were control sessions, while in the third session, the left hand was immersed in cold water at 10 °C as a conditioning stimulus. The magnitude of the R2 blink and NRS scores were compared among the sessions by 2-way ANOVA. Both the NRS score and nociceptive R2 were significantly decreased in the third session for IES, with a significant correlation between the two variables; whereas, TS-induced non-nociceptive R2 did not change among the sessions. Although the conditioning stimulus decreased the NRS score for TS, the CPM effect was significantly smaller than that for IES (p = 0.002). The present findings suggest the presence of a pain-specific CPM effect to a heterotopic noxious stimulus.

In vivo neuroimaging could be utilized as a noninvasive tool for elaborating the CNS mechanism of chronic pain and for elaborating mechanisms of potential analgesic therapeutics. A model of unilateral peripheral neuropathy was developed in the cynomolgus macaque, a species that is phylogenetically close to humans. Nerve entrapment was induced by placing a 4 mm length of polyvinyl cuff around the left common sciatic nerve. Prior to nerve injury, stimulation of the foot with a range of non-noxious von Frey filaments (1, 4, 8, 15, and 26 g) did not evoke brain activation as observed with functional magnetic resonance imaging (fMRI). Two weeks after injury, stimulation of the ipsilateral foot with non-noxious filaments activated the contralateral insula/secondary somatosensory cortex (Ins/SII) and anterior cingulate cortex (ACC). By contrast, no activation was observed with stimulation of the contralateral foot. Robust bilateral activation of thalamus was observed three to five weeks after nerve injury. Treatment with the clinical analgesic pregabalin reduced evoked activation of Ins/SII, thalamus and ACC whereas treatment with the NK1 receptor antagonist aprepitant reduced activation of the ipsilateral (left) thalamus. Twelve to 13 weeks after nerve injury, treatment with pregabalin reduced evoked activation of all regions of interest (ROI). By contrast, brain activation persisted in most ROI, except the ACC, following aprepitant treatment. Activation of the contralateral Ins/SII and bilateral thalamus was observed six months after nerve injury and pregabalin treatment suppressed activation of these nuclei. The current findings demonstrated persistent changes in CNS neurons following nerve injury as suggested by activation with non-painful mechanical stimulation. Furthermore, it was possible to functionally distinguish between a clinically efficacious analgesic drug, pregabalin, from a drug that has not demonstrated significant clinical analgesic efficacy, aprepitant. In vivo neuroimaging in the current nonhuman model could enhance translatability.

Understanding the neurophysiology underlying neonatal responses to noxious stimulation is central to improving early life pain management. In this neonatal multimodal MRI study, we use resting-state and diffusion MRI to investigate inter-individual variability in noxious-stimulus evoked brain activity. We observe that cerebral haemodynamic responses to experimental noxious stimulation can be predicted from separately acquired resting-state brain activity (n = 18). Applying this prediction model to independent Developing Human Connectome Project data (n = 215), we identify negative associations between predicted noxious-stimulus evoked responses and white matter mean diffusivity. These associations are subsequently confirmed in the original noxious stimulation paradigm dataset, validating the prediction model. Here, we observe that noxious-stimulus evoked brain activity in healthy neonates is coupled to resting-state activity and white matter microstructure, that neural features can be used to predict responses to noxious stimulation, and that the dHCP dataset could be utilised for future exploratory research of early life pain system neurophysiology. The neurophysiological basis of neonatal responses to noxious stimulation is poorly understood. Using MRI, the authors observe that neonates’ noxious-stimulus evoked brain activity is coupled to both their resting-state network activity and white matter microstructure.

Objective Transient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel expressed on a subset of sensory neurons. TRPA1 is activated by a host of noxious stimuli including pollutants, irritants, oxidative stress and inflammation, and is thought to play an important role in nociception and pain perception. TRPA1 is therefore a therapeutic target for diseases with nociceptive sensory signaling components. TRPA1 orthologs have been shown to have differential sensitivity to certain ligands. Cinnamaldehyde has previously been shown to activate sensory neurons via the selective gating of TRPA1. Here, we tested the sensitivity of cinnamaldehyde-evoked responses in mouse and guinea pig sensory neurons to the pore blocker ruthenium red (RuR). Results Cinnamaldehyde, the canonical TRPA1-selective agonist, caused robust calcium fluxes in trigeminal neurons dissociated from both mice and guinea pigs. RuR effectively inhibited cinnamaldehyde-evoked responses in mouse neurons at 30 nM, with complete block seen with 3 μM. In contrast, responses in guinea pig neurons were only partially inhibited by 3 μM RuR. We conclude that RuR has a decreased affinity for guinea pig TRPA1 compared to mouse TRPA1. This study provides further evidence of differences in ligand affinity for TRPA1 in animal models relevant for drug development.

Rationale and ObjectivePain-related factors increase risk for opioid addiction, and opioid-induced pain relief may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food.MethodsIn Experiment 1, rats self-administered fentanyl in the presence or absence of repeated intraplantar capsaicin injections in distinct contexts to model context-specific exposure to cutaneous nociception. After capsaicin-free extinction in both contexts, we tested if capsaicin would reinstate fentanyl seeking. In Experiment 2, rats self-administered heroin after intraperitoneal (i.p.) lactic acid injections to model acute visceral inflammatory pain. After lactic acid-free extinction, we tested if lactic acid would reinstate heroin seeking. In Experiment 3, we tested if repeated i.p. lactic acid or intraplantar Complete Freund’s Adjuvant (CFA; to model sustained inflammatory pain) would increase fentanyl choice over food.ResultsIn Experiments 1-2, neither capsaicin nor lactic acid reinstated opioid seeking after extinction, and lactic acid did not increase heroin-induced reinstatement. In Experiment 3, lactic acid and CFA decreased reinforcement rate without affecting fentanyl choice.ConclusionsResults extend the range of conditions across which pain-related manipulations fail to increase opioid seeking in rats and suggest that enhanced opioid-addiction risk in humans with chronic pain involves factors other than enhanced opioid reinforcement and relapse.

Provoked Vestibulodynia (PVD) is the most common vulvodynia subtype (idiopathic chronic vulvar pain). Functional magnetic resonance imaging (fMRI) studies indicate that women with PVD exhibit altered function in a number of pain modulatory regions in response to noxious stimulation, such as in the secondary somatosensory cortex, insula, dorsal midcingulate, posterior cingulate, and thalamus. However, previous neuroimaging studies of PVD have not examined periods of time before and after noxious stimulation or investigated functional connectivity among pain modulatory regions. Fourteen women with PVD and 14 matched Control participants underwent five fMRI runs with no painful stimuli interleaved randomly with five runs with calibrated, moderately painful heat stimuli applied to the thenar eminence. As recent findings indicate that pain processing begins before and continues after painful stimulation, 2-min periods were included in each run before and after the stimulus. Functional brain connectivity was assessed during both trials of Pain and No Pain stimulation for each group using structural equation modeling (SEM). Analyses of variance (ANOVAs) on connectivity values demonstrated significant main effects of study condition, and group, for connectivity among pain modulatory regions. Most of the differences between the Pain and No Pain conditions found only in the PVD group take place before (i.e., thalamus to INS, ACC to S1, thalamus to S1, and thalamus to S2) and after pain stimulation (i.e., INS to amygdala, PPC to S1, and thalamus to S2). Such differences were not observed in the Control group. These findings further support previous results indicating that women with PVD have altered pain processing compared to pain-free women.

Acute arterial strokes in children are rare but can potentially cause lasting and often permanent neurological deficits. Mechanical thrombectomy has a well-established efficacy and safety profile in adult stroke management, but in the pediatric population, it is yet to be proven efficacious and safe. We present a case of a seven-year-old male who presented with multiple episodes of generalized tonic-clonic seizures after sustaining a neck injury by falling from a trampoline. National Institutes of Health (NIH) on presentation was 21. Neurological exam revealed dilated nonreactive pupils, dysconjugate gaze, severe dysarthria, bilateral ptosis, and movement of upper and lower extremities only to noxious stimuli. Magnetic resonance imaging (MRI) of brain without contrast revealed infarcted areas in the left pons, midbrain, and cerebellar regions. Computed tomographic angiogram (CTA) of head demonstrated left vertebral artery dissection with associated complete occlusion of the distal basilar artery. Successful recanalization was achieved with mechanical thrombectomy six hours after presentation. Mechanical thrombectomy treatment resulted in a significant neurological recovery with NIH of 1. This case supports the growing evidence of the efficacy and safety of mechanical thrombectomy in children.

Objectives The prediction of patient responses to potentially painful stimuli remains a challenge in PICUs. We investigated the ability of the paintracker analgesia monitor (Dolosys GmbH, Berlin, Germany) measuring the nociceptive flexion reflex threshold, the cerebral sedation monitor bispectral index (Medtronic, Dublin, Ireland), the COMFORT Behavior, and the modified Face, Legs, Activity, Cry, Consolability Scale scores to predict patient responses following a noxious stimulus. Design Single-center prospective exploratory observational study. Setting Fourteen-bed multidisciplinary PICU at the University Children's Hospital, University Medical Center Hamburg Eppendorf, Germany. Patients Children on mechanical ventilation receiving analgesic and sedative medications. Interventions Noxious stimulation by way of endotracheal suctioning. Measurements and main results Two independent observers assessed modified Face, Legs, Activity, Cry, Consolability and COMFORT Behavior Scales scores during noxious stimulation (n = 59) in 26 patients. Vital signs were recorded immediately before and during noxious stimulation; bispectral index and nociceptive flexion reflex threshold were recorded continuously. Mean prestimulation bispectral index (55.5; CI, 44.2-66.9 vs 39.9; CI, 33.1-46.8; p = 0.007), and COMFORT Behavior values (9.5; CI, 9.2-13.2 vs 7.5; CI, 6.7-8.5; p = 0.023) were significantly higher in observations with a response than in those without a response. Prediction probability (Pk) values for patient responses were high when the bispectral index was used (Pk = 0.85) but only fair when the nociceptive flexion reflex threshold (Pk = 0.69) or COMFORT Behavior Scale score (Pk = 0.73) was used. A logistic mixed-effects model confirmed the bispectral index as a significant potential predictor of patient response (p = 0.007). Conclusions In our sample of ventilated children in the PICU, bispectral index and nociceptive flexion reflex threshold provided good and fair prediction accuracy for patient responses to endotracheal suctioning.

Understanding the molecular mechanisms of nociception has recently grown impressively. Nociception is mediated by mechanical, chemical, or microbial stimuli that evoke unpleasant feelings, alerting the host of the risk of tissue damage. Such diverse arrays of noxious stimuli trigger various escape reactions, usually altering immune homeostasis. Notably, nociceptors can recognize cytokines or pathogens via sensory molecules or innate immune receptors, participating in immune responses. Accumulating evidence suggests that activated nociceptors produce various humoral factors that affect the immune system and act like endocrine/paracrine signals. Thus, understanding the interplay between the nociceptive and immune systems may open new avenues for the development of an interdisciplinary research field, hereinafter referred to as "senso-immunology." This review will discuss the physiological relevance of the senso-immune system in the host defense context, focusing on how senso-immune research might yield novel treatments to cure pain and inflammation.

The multi‐mode pain‐perceptual system (MMPPS) is essential for the human body to perceive noxious stimuli in all circumstances and make an appropriate reaction. Based on the central sensitization mechanism, the MMPPS can switch between different working modes and thus offers a smarter protection mechanism to human body. Accordingly, before injury MMPPS can offer warning of excessive pressure with normal pressure threshold. After injury, extra care on the periphery of damage will be activated by decreasing the pressure threshold. Furthermore, the MMPPS will gradually recover back to a normal state as damage heals. Although current devices can realize basic functions like damage localization and nociceptor signal imitating, the development of a human‐like MMPPS is still a great challenge. Here, a bio‐inspired MMPPS is developed for prosthetics protection, in which all working modes is realized and controlled by mimicking the central sensitization mechanism. Accordingly, the system warns one of a potential injury, identifies the damaged area, and subsequently offers extra care. The proposed system can open new avenues for designing next‐generation prosthetics, especially make other smart sensing systems operate under complete protection against injuries., Inspired by the comprehensive protection mechanism of humans, a multi‐mode pain‐perceptual system is developed for prosthetic protection. Before an injury, the system can provide early warning. After the injury, damaged area is located and extra protection is realized, during which minor pressure can induce pain. Furthermore, the pressure threshold gradually restores to normal as the damaged area heals.