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Cerebral conditioning is defined as the mild harmful stimuli applied to the brain before ischemia (preconditioning), during ischemia (perconditioning), immediately, a few hours or days after reperfusion (postconditioning). Various noxious stimuli can precondition, percondition or postcondition the brain, including ischemia, hypoxia or anesthetics to induce tolerance to lethal ischemia/reperfusion injury. The mechanisms underlying cerebral conditioning range from sensors and transducers including extracellular neurotransmitters and receptors, intracellular signals, transcription factors and epigenetic regulation, to effectors involving physiological protection, stem cells, heat shock proteins, Bcl-2, mitochondria, ubiquitin - proteasome pathway and autophagy pathway. Based on the large number of studies conducted in animal models, researchers explore the clinical application of cerebral conditioning. Remote ischemic conditioning is considered the most applicable and clinically relevant form of cerebral conditioning. The translational research also involves development of the biomarkers of conditioning and optimization of organ transplantation. The present review summarized the recent progress in signaling pathways and clinical applications of cerebral conditioning to explore the possibility to develop a potential therapeutic strategy for the prevention and treatment of ischemic stroke.

Prior expectations can bias how we perceive pain. Using a drift diffusion model, we recently showed that this influence is primarily based on changes in perceptual decision-making (indexed as shift in starting point). Only during unexpected application of high-intensity noxious stimuli, altered information processing (indexed as increase in drift rate) explained the expectancy effect on pain processing. Here, we employed functional magnetic resonance imaging to investigate the neural basis of both these processes in healthy volunteers. On each trial, visual cues induced the expectation of high- or low-intensity noxious stimulation or signaled equal probability for both intensities. Participants categorized a subsequently applied electrical stimulus as either low- or high-intensity pain. A shift in starting point towards high pain correlated negatively with right dorsolateral prefrontal cortex activity during cue presentation underscoring its proposed role of "keeping pain out of mind". This anticipatory right dorsolateral prefrontal cortex signal increase was positively correlated with periaqueductal gray (PAG) activity when the expected high-intensity stimulation was applied. A drift rate increase during unexpected high-intensity pain was reflected in amygdala engagement and increased functional connectivity between amygdala and PAG. Our findings suggest involvement of the PAG in both decision-making bias and altered information processing to implement expectancy effects on pain. PERSPECTIVE: Modulation of pain through expectations has been linked to changes in perceptual decision-making and altered processing of afferent information. Our results suggest involvement of the dorsolateral prefrontal cortex, amygdala, and periaqueductal gray in these processes.

Abnormal central pain processing is a leading cause of pain in fibromyalgia (FM) and is perceptually characterized with the psychophysical measure of temporal summation of pain (TSP). TSP is the perception of increasingly greater pain in response to repetitive or tonic noxious stimuli. Previous neuroimaging studies have used static (i.e., summary) measures to examine the functional magnetic resonance imaging (fMRI) correlates of TSP in FM. However, functional brain activity rapidly and dynamically reorganizes over time, and, similarly, TSP is a temporally evolving process. This study was undertaken to demonstrate how a complete understanding of the neural circuitry supporting TSP in FM thus requires a dynamic measure that evolves over time.We utilized novel methods for analyzing dynamic functional brain connectivity in patients with FM in order to examine how TSP-associated fluctuations are linked to the dynamic functional reconfiguration of the brain. In 84 FM patients and age- and sex-matched healthy controls, we collected high-temporal-resolution fMRI data during a resting state and during a state in which sustained cuff pressure pain was applied to the leg.FM patients experienced greater TSP than healthy controls (mean ± SD TSP score 17.93 ± 19.24 in FM patients versus 9.47 ± 14.06 in healthy controls; P = 0.028), but TSP scores varied substantially between patients. In the brain, the presence versus absence of TSP in patients with FM was marked by more sustained enmeshment between sensorimotor and salience networks during the pain period. Furthermore, dynamic enmeshment was noted solely in FM patients with high TSP, as interactions with all other brain networks were dampened during the pain period.This study elucidates the dynamic brain processes underlying facilitated central pain processing in FM. Our findings will enable future investigation of dynamic symptoms in FM.

Nociceptive input diminishes recovery and increases lesion area after a spinal cord injury (SCI). Recent work has linked these effects to the expansion of hemorrhage at the site of injury. The current paper examines whether these adverse effects are linked to a pain-induced rise in blood pressure and/or flow. Male rats with a low-thoracic spinal cord injury were treated with noxious input [electrical stimulation (shock) or capsaicin] soon after injury. Locomotor recovery and blood pressure were assessed throughout. Tissues were collected three hours, 24 hours, or 21 days later. Both electrical stimulation and capsaicin undermined locomotor function and increased the area of hemorrhage. Changes in blood pressure/flow varied depending on type of noxious input, with only shock producing changes in blood pressure. Providing behavioral control over the termination of noxious stimulation attenuated the rise in blood pressure and hemorrhage. Pretreatment with the alpha-1 adrenergic receptor inverse agonist, prazosin, reduced the stimulation-induced rise in blood pressure and hemorrhage. Prazosin also attenuated the adverse effect noxious stimulation has on long-term recovery. Administration of the adrenergic agonist, norepinephrine, a day after injury induced an increase in blood pressure and disrupted locomotor function, but had little effect on hemorrhage. Further, inducing a rise in blood pressure/flow using norepinephrine undermined long-term recovery and increased tissue loss. Mediational analyses suggest that the pain-induced rise in blood flow may foster hemorrhage after SCI. Increased blood pressure appears to act through an independent process to adversely affect locomotor performance, tissue sparing, and long-term recovery.

Pain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.

Pain assessment is challenging in neonates. Behavioral and physiological pain scales do not assess neocortical nociception, essential to pain encoding and central pain pathway development. Functional near-infrared spectroscopy (fNIRS) can assess neocortical activation to noxious stimuli from changes in oxy-(HbO) and total-hemoglobin concentrations (HbT). This study aims to assess fNIRS nociceptive functional activation in the prefrontal cortex of neonates undergoing circumcision through changes in HbO and HbT, and the correlation between changes in fNIRS and Neonatal Infant Pain Scale (NIPS), a behavioral pain assessment scale.In healthy term neonates, HbO, HbT, and NIPS were recorded during sequential circumcision events 1-Prep before local anesthetic injection; 2-Local anesthetic injection; 3-Prep before incision; 4-Oral sucrose; 5-Incision; 6-Gomco (hemostatic device) attached; 7-Gomco twisted on; and 8-Gomco removed. fNIRS and NIPS changes after each event were assessed with Wilcoxon signed-rank test and summarized as median and interquartile range (IQR). Changes in fNIRS vs. NIPS were correlated with Spearman coefficient.In 31 neonates fNIRS increased (median [IQR] µmol/L) with noxious events: Local injection (HbO: 1.1 [0.5, 3.1], p .001; HbT: 2.3 [0.2, 7.6], p .001), Gomco attached (HbO: 0.7 [0.1, 1.7], p = .002; HbT: 0.7 [-0.2, 2.9], p = .02), and Gomco twisted on (HbO: 0.5 [-0.2, 1.7], p = .03; HbT: 0.8 [-0.1, 3.3], p = .02). fNIRS decreased with non-noxious event: Prep before incision (HbO: -0.6 [-1.2, -0.2] p .001; HbT: -1 [-1.8, -0.4], p .001). Local anesthetic attenuated fNIRS increases to subsequent sharp stimuli. NIPS increased with subsequent sharp stimuli despite local anesthetic. Although fNIRS and NIPS changed in the same direction, there was not a strong correlation between them.During neonatal circumcision, changes in fNIRS differed between different types of painful stimuli, which was not the case for NIPS, suggesting that fNIRS may complement NIPS to assess the quality of pain.

Determining the clinical efficacy of analgesic drugs in amphibians can be particularly challenging. The current study investigated whether a thermal nociceptive stimulus is useful for the evaluation of analgesic drugs in 2 amphibian species. The objectives of this study were 2-fold: 1) compare 2 models of nociception (thermal and mechanical) using 2 frog species; White's Tree Frogs (Litoria caerulea; WTF) and Northern Leopard Frogs (Lithobates pipiens; NLF) after administration of saline or morphine sulfate; and 2) evaluate antinociceptive efficacy of morphine sulfate at 2 doses in a common amphibian research species, the NLF, using a mechanical stimulus. Neither WTF nor NLF displayed consistent drug-dependent changes in withdrawal responses to a noxious thermal stimulus applied using the Hargreaves apparatus, but NLF exposed to the noxious mechanical stimulus demonstrated a significant dose-dependent antinociceptive response to morphine sulfate. These results indicate that morphine is not antinociceptive in WTF, supporting previously reported results, and demonstrate the importance of using an appropriate experimental antinociceptive test in amphibians. Our data suggest that nociception in amphibian species may be best evaluated by using mechanical nociceptive models, although species differences must also be considered.

Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study used ultra-high-field 7 tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants (N= 25, 12 male). Over 2 successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled lidocaine (placebo) and capsaicin (nocebo) were acting to modulate their pain relative to a third Vaseline (control) cream. In a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG)–rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG–RVM pathway, which in concert with other brainstem sites likely influences the experience of pain by modulating activity at the level of the dorsal horn.SIGNIFICANCE STATEMENTUnderstanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation; however, because of the small size and complex organization of the nuclei, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of antinociceptive and pro-nociceptive effects. We used ultra-high-field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation.

Transient receptor potential ankyrin 1 (TRPA1) channel, as a nonselective ligand-gated cation channel robustly in dorsal root ganglion sensory neurons, is implicated in sensing noxious stimuli and nociceptive signaling. However, small-molecule tools targeting TRPA1 lack temporal and spatial resolution, limiting their use for validation of TRPA1 as a therapeutic target for pain. In our previous work, we found that 4,4'-(diazene-1,2-diyl)dianiline (AB1) is a photoswitchable TRPA1 agonist, but the poor water solubility and activity hinder its further development. Here, we report a series of specific and potent azobenzene-derived photoswitchable TRPA1 agonists (series 1 and 2) that enable optical control of the TRPA1 channel. Two representative compounds 1g and 2c can alleviate capsaicin-induced pain in the cheek model of mice through channel desensitization but not in TRPA1 knockout mice. Taken together, our findings demonstrate that photoswitchable TRPA1 agonists can be used as pharmacological tools for study of pain signaling.

Background Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain. Methods Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block. Results A reduction of the total fractional power in both groups—specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex—was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34). Conclusions These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Gluteal syndrome (GS), a new low-back-pain subtype mimicking sciatica, has been included in the 11th Revision of the International Classification of Diseases (ICD-11). Low back pain is a symptom, not a disease, and the main problem associated with it is pain complexity. A plausible pain generator of gluteal syndrome is the central sensitization process and the therapeutic target area, which are trigger points located within the gluteal muscles. It has been hypothesized that dysregulated immune and autonomic nervous systems (ANS) are involved in central sensitization development. Changes in ANS regulation, mainly through the sympathetic branch, provoke nociceptor activation indirectly by a vasoconstriction–vasodilatation imbalance, or directly by sympathetic–nociceptor activation resulting in widespread pain, hyperalgesia, and allodynia. The minimally invasive procedure (MIP) uses thermography to confirm a completely new biological phenomenon, which suggests a pathological autonomic response to noxious stimuli and can possibly become an objective marker of some nociplastic pain subtypes related to trigger points. This review provides the biological and technical rationale for the automation of the MIP—a possible future diagnostic tool for an objective gluteal syndrome confirmation.

Background Patients with chronic pain exhibit hypervigilance (heightened responsiveness to stimuli) to innocuous auditory stimuli as well as noxious stimuli. "Generalized hypervigilance" suggests that individuals who show heightened responsiveness to one sensory system also show hypervigilance to other modalities. However, research exploring the existence of generalized hypervigilance in healthy subjects is limited. Methods We investigated whether hypervigilance to pain is associated with auditory stimuli in healthy subjects using the pain vigilance and awareness questionnaire (PVAQ) and auditory change-related cortical responses (ACRs). ACRs are thought to reflect a change detection system, based on preceding sensory memory. We recorded ACRs under conditions that varied in terms of the accumulation of sensory memory as follows: short-ACR, with short preceding continuous stimuli and long-ACR, with long preceding continuous stimuli. In addition, the attention to pain (PVAQ-AP) and attention to changes in pain (PVAQ-ACP) subscales were evaluated. Results Amplitudes of long-ACR showed significant positive correlations with PVAQ-ACP, whereas those of short-ACR did not show any significant correlations. Conclusions Generalized hypervigilance may be observed even in healthy subjects. ACR may be a useful index to evaluate the hypervigilance state in the human brain.

Primary sensory neurons are a heterogeneous population of cells able to respond to both innocuous and noxious stimuli. Like most neurons they are highly compartmentalised, allowing them to detect, convey and transfer sensory information. These compartments include specialised sensory endings in the skin, the nodes of Ranvier in myelinated axons, the cell soma and their central terminals in the spinal cord. In this review, we will highlight the importance of these compartments to primary afferent function, describe how these structures are compromised following nerve damage and how this relates to neuropathic pain.

Background Recording spontaneous and evoked activities by means of unitary extracellular recordings and local field potential (LFP) are key understanding the mechanisms of neural coding. The LFP is one of the most popular and easy methods to measure the activity of a population of neurons. LFP is also a composite signal known to be difficult to interpret and model. There is a growing need to highlight the relationship between spiking activity and LFP. Here, we hypothesized that LFP could be inferred from spikes under evoked noxious conditions. Method Recording was performed from the medullary dorsal horn (MDH) in deeply anesthetized rats. We detail a process to highlight the C-fiber (nociceptive) evoked activity, by removing the A-fiber evoked activity using a model-based approach. Then, we applied the convolution kernel theory and optimization algorithms to infer the C-fiber LFP from the single cell spikes. Finally, we used a probability density function and an optimization algorithm to infer the spikes distribution from the LFP. Results We successfully extracted C-fiber LFP in all data recordings. We observed that C-fibers spikes preceded the C-fiber LFP and were rather correlated to the LFP derivative. Finally, we inferred LFP from spikes with excellent correlation coefficient (r = 0.9) and reverse generated the spikes distribution from LFP with good correlation coefficients (r = 0.7) on spikes number. Conclusion We introduced the kernel convolution theory to successfully infer the LFP from spikes, and we demonstrated that we could generate the spikes distribution from the LFP.

Objective Many studies have examined the effectiveness of transcranial direct current stimulation (tDCS) on human pain perception in both healthy populations and pain patients. Nevertheless, studies have yielded conflicting results, likely due to differences in stimulation parameters, experimental paradigms, and outcome measures. Human experimental pain models that utilize indices of pain in response to well-controlled noxious stimuli can avoid many confounds present in clinical data. This study aimed to assess the robustness of tDCS effects on experimental pain perception among healthy populations. Methods We conducted three meta-analyses that analyzed tDCS effects on ratings of perceived pain intensity to suprathreshold noxious stimuli, pain threshold and tolerance. Results The meta-analyses showed a statically significant tDCS effect on attenuating pain-intensity ratings to suprathreshold noxious stimuli. In contrast, tDCS effects on pain threshold and pain tolerance were statistically non-significant. Moderator analysis further suggested that stimulation parameters (active electrode size and current density) and experimental pain modality moderated the effectiveness of tDCS in attenuating pain-intensity ratings. Conclusion The effectiveness of tDCS on attenuating experimental pain perception depends on both stimulation parameters of tDCS and the modality of experimental pain. Significance This study provides some theoretical basis for the application of tDCS in pain management.

Nociception refers to the process of encoding and processing noxious stimuli. Its monitoring can have potential benefits. Under anesthesia, nociceptive signals are continuously generated to cause involuntary effects on the autonomic nervous system, reflex movement, and stress response. Most available systems depend on the identification and measurement of these indirect effects to indicate nociception-antinociception balance. Despite advances in monitoring technology and availability, their limitations presently override their benefits. Hence, their utility and applicability in present-day anesthesia care is uncertain. Future technologies might allow automated closed-loop multimodal anesthesia systems, which includes the components of hypnosis and analgesic balance for a patient.

Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior.

Clinical relevance The discovery of an accommodative response to ocular surface stimulation could inform clinicians and patients that optical effects may occur due to ocular discomfort and perhaps an assessment of the accommodative system after carrying out interventions impacting the ocular surface, may be warranted. Background There have been no previous reports evaluating the effect of noxious stimulation on accommodation. Here, the accommodative response of healthy participants after the application of noxious corneal stimulation is characterised. Methods A computerised Belmonte pneumatic esthesiometer was used to determine detection thresholds (using ascending method of limits), and to randomly deliver mechanical and chemical stimuli from levels of detection threshold to twice the threshold in 50% steps, to the central cornea of 15 healthy subjects. For each suprathreshold stimulus, accommodative and pupil responses were measured with a validated eccentric infrared photorefractor. Quantitative differences in accommodative/pupil response, stimulus modality/intensity and left/right eye were analysed using repeated measures ANOVA. Tukey HSD tests were used for all post hoc analyses. Results Accommodation increased from baseline as the corneal apical stimulus intensity increased. This happened regardless of whether mechanical or chemical stimulation occurred (ANOVA, p 0.05) and chemical stimulation (ANOVA, p > 0.05). Conclusion Noxious stimulation of the cornea seems to produce a dose-dependent increase in the accommodative response in the eyes but not a dose-dependent pupil response.

BACKGROUND Exposure to stressful experiences is often accompanied by suppressing pain perception, referred to as stress-induced analgesia. The neuropeptides orexins are essential in regulating the mechanism that responds to stressful and painful stimuli. Meanwhile, the ventral tegmental area (VTA), as a part of descending pain inhibitory system, responds to noxious stimuli. This study aimed to investigate the role of intra-VTA administration of orexin receptor antagonists on stress-induced antinociceptive responses in the animal model of acute pain. METHOD Ninety-three adult Wistar rats weighing 230-250 g were unilaterally implanted by a cannulae above the VTA. Animals were pretreated with different doses (1, 3, 10 and 30 nM/0.3 μl) of SB334867 as the orexin-1 receptor antagonist and TCS OX2 29 as the orexin-2 receptor antagonist into the VTA, just 5 min before 6 min exposure to forced swim stress (FSS). Nociceptive threshold was measured using the tail-flick test as a model of acute pain. RESULTS The results showed that exposure to FSS could significantly increase analgesic responses. Moreover, intra-VTA administration of SB334768 and TCS OX2 29 blocked the antinociceptive effect of FSS in the tail-flick test. CONCLUSION The findings suggest that OX1 and OX2 receptors in the VTA might modulate the antinociceptive behaviours induced by FSS in part. SIGNIFICANCE Acute exposure to physical stress suppresses pain-related behaviors in the animal model of acute pain. Blockade of the OX1 and OX2 receptors in the VTA attenuates antinociceptive responses induced by FSS. The contribution of the OX2 receptors in the VTA is more predominant than OX1 receptors in stress-induced analgesia.

The cerebral integration of somatosensory inputs from multiple sources is essential to produce adapted behaviors. Previous studies suggest that bilateral somatosensory inputs interact differently depending on stimulus characteristics, including their noxious nature. The aim of this study was to clarify how bilateral inputs evoked by noxious laser stimuli, noxious shocks, and innocuous shocks interact in terms of perception and brain responses. The experiment comprised two conditions (right-hand stimulation and concurrent stimulation of both hands) in which painful laser stimuli, painful shocks and non-painful shocks were delivered. Perception, somatosensory-evoked potentials (P45, N100, P260), laser-evoked potentials (N1, N2 and P2) and event-related spectral perturbations (delta to gamma oscillation power) were compared between conditions and stimulus modalities. The amplitude of negative vertex potentials (N2 or N100) and the power of delta/theta oscillations were increased in the bilateral compared with unilateral condition, regardless of the stimulus type (P

Background: Inadequate management of intraoperative pain poses a risk of postoperative chronic pain complications. The use of preemptive analgesia before the onset of surgical incision stimulation was considered to prevent central sensitization. Clinical research around the terms of preemptive analgesia needs to be proven by nociception-based intraoperative monitoring. An objective modality with EEG guidance can provide information on noxious stimuli.Objective: To determine the effectiveness of ketamine and fentanyl administration as preemptive analgesia measured by qNOX scores through the CONOX tool.Methods: This study is a single-blinded randomized experiment with the division of two groups: control and treatment. The control group received preemptive fentanyl, and the treatment group received preemptive ketamine and fentanyl. Then the qNOX score was assessed during operation.Result: The qNOX score of the treatment group in minute-15 and 30 was lower than the control group (p = 0.007; p = 0.025), while in the minute-90 it was higher than the control group (p = 0.001). The mean first 1-hour qNOX score was lower in the treatment group (p

Congenital Insensitivity to Pain (CIP) is a rare disorder that is characterized by the inability to perceive pain. It is caused by bi-allelic inactivating mutations in the SCN9A gene, which encodes the pore-forming α-subunit of the nerve voltage-gated sodium channel (Nav1.7). Patients with CIP are unable to feel pain from noxious stimuli, including heat, but all other peripheral somatosensory modalities function normally. Often anosmia is present as an additional feature. We reported a patient with CIP caused by compound heterozygous SCN9A mutations: a novel in-frame deletion of exon 7 and a novel frameshift mutation. The identification of these mutations expands the spectrum of mutations associated with CIP.

The respiratory epithelium is one of the primary interfaces between the body's immune system and the external environment. This review discusses the innate and adaptive immunomodulatory effects of the respiratory epithelium, highlighting the physiologic immune responses associated with health and the disease-causing sequelae when these physiologic responses go awry. Airway macrophages, dendritic cells, and innate lymphoid cells are discussed as orchestrators of physiological and pathological innate immune responses and T cells, B cells, mast cells, and granulocytes (eosinophils and neutrophils) as orchestrators of physiologic and pathologic adaptive immune responses. The interplay between the airway epithelium and the varied immune cells as well as the interplay between these immune cells is discussed, highlighting the importance of the dose of noxious stimuli and pathogens in immune programming and the timing of their interaction with the immune cells that determine the pattern of immune responses. Although each cell type has been researched individually, this review highlights the need for simultaneous temporal investigation of immune responses from these varied cells to noxious stimuli and pathogens.

Characteristics of noxious stimuli and personal attributes shape our experience of pain, but only few studies have rigorously tried to characterize which specific traits impact pain processing. We will discuss the recent article by Firouzian et al. that tries to identify the impact of both positively and negatively regarded personal traits on conditioned pain modulation (CPM): resilience and catastrophization. The authors showed sex-dependent correlation of CPM varying with personal traits as well as characteristics of the conditioning stimulus: unpleasantness and salience.

To test the hypothesis that, in comparison with control, experimental noxious stimulation of the right masseter muscle would result in significant changes in the firing rates, thresholds, and recruitment orders of single-motor units (SMUs) of the nonpainful, synergistic right anterior temporalis muscle during goal-directed isometric biting task performance.Twenty healthy volunteers received an infusion of hypertonic saline (HS; 5% sodium chloride) into the right masseter to produce pain intensity of 40 to 60 on a 100-mm visual analog scale (VAS). Isotonic saline (IS) infusion was a control. Standardized biting tasks were performed with an intraoral force transducer, and intramuscular electromyographic activity was recorded from the right anterior temporalis muscle. Tasks (slow and fast ramp biting tasks, two-step biting task) were performed in 3 blocks: baseline, HS infusion, and IS infusion. Across blocks, SMU thresholds and firing rates were statistically compared, and SMU recruitment sequences were qualitatively compared. Statistical significance was set at P.05.No significant differences (P.05) were noted between HS and IS infusion blocks in thresholds or firing rates of anterior temporalis SMUs. Individual SMUs showed increases or decreases in thresholds or firing rates or changes in recruitment sequences mostly during HS compared to IS infusion.The reorganization of SMU activity that has been suggested to occur in both painful and nonpainful agonist jaw muscles may involve not only recruitments and de-recruitments of SMUs, but may also extend to more subtle increases and/or decreases in firing rates, thresholds, and recruitment sequences of individual SMUs in the nonpainful synergistic muscles.

Neuropathic pain is a very complex chronic pain state, the detailed molecular mechanisms of which remain unclear. In the present study, Shank3 was found to play an important role in neuropathic pain in rats following spared nerve injury (SNI). Shank3 was upregulated in the spinal dorsal horn of rats subjected to SNI, and mechanical hypersensitivity to noxious stimuli in these rats could be alleviated by knock down of Shank3. Shank3 also interacted with hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) and promoted the expression of HCN2 in central neurons of the spinal dorsal. Together with the SNI-dependent increase of HCN2, we also found that the postsynaptic protein of excitatory synapse (PSD95) was increased in rats following SNI. Taken together, our results showed that Shank3 modulated neuropathic pain by facilitating the SNI-dependent increase of HCN2 and the expression of PSD95 in spinal dorsal horn neurons. Our findings revealed new synaptic remodeling mechanisms linking Shank3 with neuropathic pain.

Acutely, pain is protective. It promotes escape from, and future avoidance of, noxious stimuli through strong and often lifetime associative memories. However, with persistent acute pain or when pain becomes chronic, these memories can promote negative emotions and poor decisions often associated with deleterious behaviors. In this review, we discuss how preclinical studies can provide insights into the relationship between cognition and chronic pain. We also discuss the concept of pain as a cognitive disorder and new strategies for treating chronic pain that emphasize inhibiting the formation of pain memories or promoting “forgetting” of established pain memories.

The effects of expectations on pain perception are often studied using large differences in pain probabilities between experimental conditions, although they may be far more subtle in clinical contexts and, therefore, more difficult to detect. The current study aimed to investigate at which point subtle differences in pain probabilities can be detected and lead to differentiable expectations and perceptions. Furthermore, we investigated whether instructions can aid learning from experience and enhance subsequent pain modulatory effects. During a predictive learning task, participants were presented with 5 different cues, followed by either a high and low noxious stimulus. They learned about the different cue-stimulus contingencies either solely through experience (LEARN, N = 40) or a combination of experience and explicit information about the cue-stimulus contingencies (INSTRUCT, N = 40). We found that without explicit information, picking up the different pain probabilities was challenging, while explicit instruction significantly improved their detection. As revealed by drift diffusion modeling, learning from experience was insufficient for the development of a bias towards low pain even when it was highly likely. By contrast, when explicit information was provided, perception became more nuanced with the direction and extent of bias, capturing the subtle differences in pain probabilities. These findings highlight that the use of instructions to foster the detection of subtle pain improvements during pain treatment to enhance their cognitive pain modulatory effects warrant further investigation. ispartof: Pain vol:163 issue:1 pages:137-145 ispartof: location:United States status: published

This study aim to examine the hypothesis that repetitive painful stimuli during infancy will alter pain sensitivity and impair learning and memory during adulthood and that saccharin will prevent this through its analgesic effect. Naltrexone is used to examine if saccharin effect is mediated via the endogenous opioid system. Pain in rat pups was induced via needle pricks of the paws on day 1 of their birth (P0). All treatments/ manipulations started on day 1 and continued for 2 weeks. The radial arm water maze (RAWM) test was used to assess learning and memory. Pain threshold through foot-withdrawal response to a hot plate was also assessed. At the end of behavioral tests, animals were killed, hippocampus was dissected, and hippocampal levels of β-endorphin, enkephalin, and brain-derived neurotropic factor (BDNF) were assessed using ELISA. Naltrexone and saccharin combined normalized noxious stimulation induced increased pain sensitivity later in life. Furthermore, naltrexone and saccharin together mitigated the deficiency in learning and memory induced by noxious stimulation. Saccharin treatment prevented reduction in hippocampal enkephalin. Additionally, saccharin prevented hippocampal noxious stimulation induced BDNF decrement. Saccharin prevented long-term memory impairment during adulthood induced by repeated neonatal pain via mechanisms that appear to involve BDNF. Interestingly, naltrexone did not antagonize the effects of saccharin, instead naltrexone augmented saccharin effects.

Study Design: In this study, we decided to change the activity of periaqueductal gray (PAG)'s metabotropic glutamate receptors subtype 8 (mGluR8) by means of its specific agonist, (S)-3,4-dicarboxyphenylglycine (DCPG), and by knock downing it with mGluR8 siRNA. We then evaluated the changes in animal pain threshold levels in the face of painful thermal stimuli (thermal hyperalgesia).Purpose: Although several mechanisms have been examined for central neuropathic pain, researchers have so far failed to find the precise mechanism for the development and progression of this type of pain. Hyperalgesia is one of the most important complications of central neuropathic pain and there is not a consensus among researchers about the exact cause of this complication. In this study, we investigated the effect of activation of the PAG region mGluR8 on the threshold of pain response to thermal noxious stimulus in rats and measured mGluR8 expression.Overview of Literature: Spinal cord injury (SCI) produces an decrease in mGluR2/3 expression in the injured and vehicle-treated groups compared to normal levels, APDC and L-AP4 treated groups had higher expression levels of mGluR2/3. These findings suggesting that the level of mGluR expression after SCI may modulate nociceptive responses.Methods: Male Wistar rats were randomly assigned to five groups (n=10 per group). The clip compression injury model was used to induce chronic central neuropathic pain. Three weeks after SCI, DCPG, siRNA, or normal saline were administered to the intra-ventrolateral PAG region. Withdrawal threshold to the noxious thermal stimulus (e.g., heat hyperalgesia) was assessed through the tail-flick test. In order to assure involvement of this receptor, pain responses were compared with mice that received GRM8 siRNA.Results: We found that the mGluR8 agonist DCPG increased lead to an increased expression of mGluR8 in the PAG region. We also found that SCI can decrease the threshold of response to painful thermal stimuli; however, activation of mGluR8 with DCPG agonist did not significantly improve the tail-flick response.Conclusions: The results revealed that activation of mGluR8 in PAG is not capable of improving the thermal hyperalgesia threshold. Based on the decreased expression of mGluR8 after SCI induced by clip compression injury and its significant increase after treatment of siRNA against mGluR8, this method might still hold promise as an effective treatment of neuropathic pain. It can be concluded that increased expression of mGluR8 is due to the fact that DCPG prevents the death of neurons that express these receptors.

Small ruminants are increasing in popularity as production and companion animals in the United States, and among sheep, goats, and camelids there are many disease processes and management techniques that have the potential to result in painful or noxious stimuli. In these species, many medications and therapeutic techniques can be used to reduce or eliminate the long-term consequences of pain. In this second portion of the review, we focus on the application of pain management in these species. These strategies include mono- and multimodal and the use of precision pain management, such as epidural drug administration, regional perfusions, and transdermal applications.

Nociception is the neuronal process of encoding noxious stimuli and could be modulated at peripheral, spinal, brainstem, and cortical levels. At cortical levels, several areas including the anterior cingulate cortex (ACC), prefrontal cortex (PFC), ventrolateral orbital cortex (VLO), insular cortex (IC), motor cortex (MC), and somatosensory cortices are involved in nociception modulation through two main mechanisms: (i) a descending modulatory effect at spinal level by direct corticospinal projections or mostly by activation of brainstem structures (i.e. periaqueductal grey matter (PAG), locus coeruleus (LC), the nucleus of raphe (RM) and rostroventral medulla (RVM)); and by (ii) cortico-cortical or cortico-subcortical interactions. This review summarizes evidence related to the participation of the aforementioned cortical areas in nociception modulation and different neurotransmitters or neuromodulators that have been studied in each area. Besides, we point out the importance of considering intracortical neuronal populations and receptors expression, as well as, nociception-induced cortical changes, both functional and connectional, to better understand this modulatory effect. Finally, we discuss the possible mechanisms that could potentiate the use of cortical stimulation as a promising procedure in pain alleviation.