Nociceptive Stimuli Research Articles

Pathophysiological mechanisms of persistent orofacial pain.

Nociceptive stimuli to the orofacial region are typically received by the peripheral terminal of trigeminal ganglion (TG) neurons, and noxious orofacial information is subsequently conveyed to the trigeminal spinal subnucleus caudalis and the upper cervical spinal cord (C1-C2). This information is further transmitted to the cortical somatosensory regions and limbic system via the thalamus, which then leads to the perception of pain. It is a well-established fact that the presence of abnormal pain in the orofacial region is etiologically associated with neuroplastic changes that may occur at any point in the pain transmission pathway from the peripheral to the central nervous system (CNS). Recently, several studies have reported that functional plastic changes in a large number of cells, including TG neurons, glial cells (satellite cells, microglia, and astrocytes), and immune cells (macrophages and neutrophils), contribute to the sensitization and disinhibition of neurons in the peripheral and CNS, which results in orofacial pain hypersensitivity.

Possible Effects of Capsaicin (Chili Pepper) on the Oral Health.

Background:Capsaicin binds the TRPV1 (transient receptor potential vanilloid), desensitizing the pain fibers that become insensitive to nociceptive stimuli. For this fact that the capsaicin has antipain and antiinflammatory properties, few studies verify possible harmful effects, especially with its use in high amounts. The aim of this study is to check salivary nitric oxide (NO) and malondialdehyde (MDA) as indicators of its possible oral health alterations.Methods:The protocol calls for twelve volunteers to eat 20 g of sausage with a high content of chili pepper and capsaicin. The study analyzes their salivary concentration of NO and MDA and in control group, 2 min, 1 h, and 1.5 h after ingestion. The U-Mann Whitney Calculator Test statistically analyzes these results.Results:Immediately after eating, there is a significant increase of NO and MDA vs control: P value is 0.03752 and 0.03236, respectively. The values of NO and MDA vs control remain higher after 1 h: P value is 0.04036 and 0.0466, respectively, to return to normality after 1.5 h.Discussion:This study shows that capsaicin increases the simultaneous production of MDA and NO. It is possible to hypothesize that MDA derives mainly from the inflammatory process up-regulated by COX-2, generated by capsaicin. We hypothesize instead that the excess of capsaicin inhibits and reduces the number of TRPV1, which produces an excess of NO and generates nitrosative stress. NO reacts with O2 to form hydroxyl radicals (OH) and H2O, or with superoxide anions to form MDA.Conclusions:The results of this study clearly show that the use not necessarily excessive of chili leads to developing an inflammatory process.

Evoking the Withdrawal Reflex via Successive Needle-Pricking on the Plantar and Dorsal Aspect of the Foot Increases the FMA of the Lower Limb for Poststroke Patients in Brunnstrom Stage III: A Preliminary Study.

The withdrawal reflex is a defensive reaction to nociceptive stimuli and can be used to regulate locomotor gait during rehabilitation. We investigated the effect of successive needle-pricking of the plantar and dorsal foot surfaces on poststroke lower limb function. Thirty-five hemiplegic patients, within one month after primary stroke, with an affected lower limb (Brunnstrom stage III) were randomly divided into intervention and control groups. Both groups received routine drug treatment, rehabilitation training, and upper limb acupuncture treatment on the hemiplegic side. The control group also received routine acupuncture on the hemiplegic side of the lower limb, while the intervention group received successive needle-pricking on the sole and instep of both the unaffected and affected side feet. Outcomes were assessed before inception (D0) and after three (D3) and six (D6) treatment days, using Brunnstrom stage (Ueda assessment), total Fugl–Meyer lower extremity assessment (FMA-LE) and its subscores (FMA-LE-ss), active lower limb range of motion (AROM-LL), Modified Ashworth Scale Score (MAS-LL), and manual muscle testing (MMT-LL). The Brunnstrom stage was better in the intervention group than in the control group at both D3 and D6 (P < 0.01). The total FMA-LE score and sections B, C, D, and G FMA-LE-ss were significantly better in the intervention group than in the control group at D3 and D6 (P < 0.05). The AROM-LL hip and knee flexion and hip extension improved more in the intervention group than in the control group (P < 0.05). In the intervention group, MAS-LL hip flexion significantly improved at D6 (P < 0.01). Improvement in lower limb joints on the MMT-LL in the intervention group exceeded that in the control group at D6 (P < 0.01). Successive needle-pricking on the plantar and dorsal foot aspects of Brunnstrom stage III in poststroke patients contributed to rapid lower limb motor function improvement via the withdrawal reflex. This trial is registered with ChiCTR1900020633.

3D anatomical model for teaching canine lumbosacral epidural anesthesia.

Purpose To develop a 3D anatomical model for teaching canine epidural anesthesia (3DMEA) and to assess its efficacy for teaching and learning prior to the use of live animals.Methods The creation of 3DMEA was based on 3D optical scanning and 3D printing of canine bone pieces of the fifth to the seventh lumbar vertebrae, sacrum and pelvis. A total of 20 male dogs were scheduled for castration. 20 veterinary students watched a video showing epidural anesthesia in dogs before the clinical attempt and were assigned to control or 3DMEA groups. Students in the 3DMEA group trained in the model after the video. For the clinical trial, the epidural procedure was performed by students under the veterinary supervision. When observed the absence of response to nociceptive stimuli, the epidural was considered successful. Then, all students answered a questionnaire evaluating the main difficulty founded in the technique and its degree of difficulty.Results The 3DMEA group reported a lower degree of difficulty to perform the epidural anesthesia technique when compared with the control group (p=0.0037). The 3DMEA reproduced the anatomical structures, allowing the perception of the distance of needle in relation to the iliac prominences during epidural anesthesia. Its mobility allowed simulation of the animal in standing position and sternal recumbency.Conclusion The use of 3DMEA demonstrated greater efficacy in the execution of the technique, being effective in the teaching and learning process before the epidural anesthesia in live animals.

39: Virtual Reality reduces pain in laboring women: a randomized controlled trial

Virtual reality (VR) represents a potential method for easing labor pain. By stimulating the visual cortex while engaging other senses, VR modulates the user’s processing of nociceptive stimuli; head-to-head trials show that VR achieves similar or greater analgesia as hydromorphone. The aim of this randomized controlled trial (RCT) is to evaluate whether VR is effective in reducing pain in laboring women. We conducted an open-label, RCT of nulliparous, term women in labor. We included women with a pain score of 4-7 having contractions at least every 5 minutes. We excluded women who had received any pharmacologic pain relief including epidural or with contraindications to VR use. Participants were randomized to up to 30 minutes of either VR or no intervention (Control). Our primary outcome was the difference in differences from pre to post intervention pain score. Prespecified secondary outcomes included pain scores, duration of intervention use, pharmacologic analgesia use, vitals, and obstetric outcomes. We used minimum clinically important difference for sample size calculations which for subjects starting with a baseline pain score of 40-70 mm is 13 mm. With an 80% power and 2-sided alpha 0.05 starting from a baseline median pain of 55 mm, we would require 40 total subjects. From 3/2018 to 2/2019, 40 patients were enrolled in and completed the study; 19 were randomized to Control and 21 to VR. Half were inductions and all were latent phase with mean dilatation pre-intervention of 2.5 cm (Control) and 2.8 cm (VR). For the primary outcome – difference in pain score following the intervention – those assigned to the Control arm had a statistically significant increase in pain of +0.58 while receiving VR had a significant reduction in pain of -0.52. (p = 0.03) (Figure 1). Post-intervention heart rate was also higher in the Control arm (86.8 vs 76.3, p = 0.01). Other secondary outcomes did not differ (Table 1). In our study, we found that VR was effective for reducing pain in women in labor compared to those receiving no intervention.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

A modality-specific dysfunction of pain processing in schizophrenia.

Clinical observations showed that schizophrenia (SCZ) patients reported little or no pain under various conditions that are commonly associated with intense painful sensations, leading to a higher risk of morbidity and mortality. However, this phenomenon has received little attention and its underlying neural mechanisms remain unclear. Here, we conducted two experiments combining psychophysics, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI) techniques to investigate neural mechanisms of pain insensitivity in SCZ patients. Specifically, we adopted a stimulus–response paradigm with brief stimuli of different sensory modalities (i.e., nociceptive, non‐nociceptive somatosensory, and auditory) to test whether pain insensitivity in SCZ patients is supra‐modal or modality‐specific, and used EEG and fMRI techniques to clarify its neural mechanisms. We observed that perceived intensities to nociceptive stimuli were significantly smaller in SCZ patients than healthy controls, whereas perceived intensities to non‐nociceptive somatosensory and auditory stimuli were not significantly different. The behavioral results were confirmed by stimulus‐evoked brain responses sampled by EEG and fMRI techniques, thus verifying the modality‐specific nature of the modulation of nociceptive information processing in SCZ patients. Additionally, significant group differences were observed in the spectral power of alpha oscillations in prestimulus EEG and the seed‐based functional connectivity in resting‐state fMRI (seeds: the thalamus and periaqueductal gray that are key nodes in ascending and descending pain pathways respectively), suggesting a possible contribution of cortical–subcortical dysfunction to the phenomenon. Overall, our study provides insight into the neural mechanisms of pain insensitivity in SCZ and highlights a need for systematic assessments of their pain‐related diseases.

Efficacy of multimodal analgesic treatment of severe traumatic acute pain in mice pretreated with chronic high dose of buprenorphine inducing mechanical allodynia

Managing severe acute nociceptive pain in buprenorphine-maintained individuals for opioid use disorder management is challenging owing to the high affinity and very slow dissociation of buprenorphine from μ-opioid receptors that hinders the use of full agonist opioid analgesics.In a translational approach, the aim of this study was to use an animal setting to investigate the effects of a chronic high dose of buprenorphine treatment on nociceptive thresholds before and after applying a severe acute nociceptive traumatic surgery stimulus and to screen postoperative pharmacological analgesic strategies.A chronic treatment of mice with a high dose of buprenorphine (BUP HD, 2 × 200 μg/kg/day; i.p.) revealed significant mechanical allodynia. One and two days after having discontinued buprenorphine administration and having induced a severe nociceptive acute pain by a closed tibial fracture, acute administration of morphine at a dose which has analgesic effects in absence of pretreatment (4.5 mg/kg; i.p.), was ineffective to reduce pain in the BUP HD group. However, mimicking multimodal analgesia strategy used in human postoperative context, the combination of morphine (administered at the same dose) with a NMDA receptor antagonist (ketamine) or an NSAID (ketoprofen) produced antinociceptive responses in these animals.The mouse model of closed tibial fracture could be useful to identify analgesic strategies of postoperative pain for patients with chronic exposure to opioids and suffering from hyperalgesia.

Low-Intensity Photobiomodulation Decreases Neuropathic Pain in Paw Ischemia-Reperfusion and Spared Nervus Ischiadicus Injury Experimental Models.

There is a wide range of animal models available today for studying chronic pain associated with a variety of etiologies and an extensive list of clinical manifestations of peripheral neuropathies. Photobiomodulation is a new tool for the treatment of pain in a convenient, noninvasive way. The aim of this work is to elucidate the effects of infrared light-emitting diodes (LEDs) on behavioral responses to nociceptive stimuli in chronic pain models. Forty-eight Swiss male mice weighing 25 to 35 g were used. Two chronic pain models, ischemia-reperfusion (IR) and spared spinal nerve injury, were performed and then treated with infrared LED irradiation (390 mW, 890 nm, 17.3 mW/cm2 , 20.8 J/cm2 , for 20 minutes). The behavioral tests used were a mechanical hypersensitivity test von Frey test) and a cold allodynia test (acetone test). The results showed that, in the IR model, the infrared LED had a significant effect on mechanical stimulation and cold allodynia on every day of treatment. In the spared nerve injury model, an analgesic effect was observed on every treatment day (when started on the 3rd and 7th days after the surgery). In both models, the effect was abolished when the treatment was interrupted. These findings suggest that photobiomodulation therapy may be a useful adjunct treatment for chronic pain.

Music Reduces Pain Unpleasantness: Evidence from an EEG Study.

BackgroundMusic is sometimes used as an adjunct to pain management. However, there is limited understanding of by what means music modulates pain perception and how the brain responds to nociceptive inputs while listening to music, because clinical practice typically involves the coexistence of multiple therapeutic interventions. To address this challenge, laboratory studies with experimental and control conditions are needed.MethodsIn the present investigation, we delivered nociceptive laser stimuli on 30 participants under three conditions – participants were sitting in silence, listening to their preferred music, or listening to white noise. Differences among conditions were quantified by self-reports of pain intensity and unpleasantness, and brain activity sampled by electroencephalography (EEG).ResultsCompared with the noise and silence conditions, participants in the music condition reported lower ratings on pain unpleasantness, as reflected by reduced brain oscillations immediately prior to the nociceptive laser stimulus at frequencies of 4–15 Hz in EEG. In addition, participants showed smaller P2 amplitudes in laser-evoked potentials (LEPs) when they were listening to music or white noise in comparison to sitting in silence. These findings suggest that a general modulation effect of sounds on pain, with a specific reduction of pain unpleasantness induced by the positive emotional impact.ConclusionMusic may serve as a real-time regulator to modulate pain unpleasantness. Results are discussed in view of current understandings of music-induced analgesia.

Association of Inflammation With Pronociceptive Brain Connections in Rheumatoid Arthritis Patients With Concomitant Fibromyalgia.

Rheumatoid arthritis (RA) patients with concomitant fibromyalgia (FM) exhibit alterations in brain connectivity synonymous with central sensitization. This study was undertaken to investigate how peripheral inflammation, the principal nociceptive stimulus in RA, interacts with brain connectivity in RA patients with FM. RA patients with concomitant FM and those without FM (FM+ and FM-, respectively; n = 27 per group) underwent functional connectivity magnetic resonance imaging. Seed-to-whole-brain functional connectivity analyses were conducted using seeds from the left mid/posterior insula and left inferior parietal lobule (IPL), which are regions that have been previously linked to FM symptoms and inflammation, respectively. The association between functional connectivity and erythrocyte sedimentation rate (ESR) was assessed in each group separately, followed by post hoc analyses to test for interaction effects. Cluster-level, family-wise error (FWE) rates were considered significant if the P value was less than 0.05. The group of RA patients with FM and those without FM did not differ by age, sex, or ESR (P > 0.2). In FM+ RA patients, increased functional connectivity of the insula-left IPL, left IPL-dorsal anterior cingulate, and left IPL-medial prefrontal cortex regions correlated with higher levels of ESR (all FWE-corrected P < 0.05). Post hoc interaction analyses largely confirmed the relationship between ESR and connectivity changes as FM scores increased. We report the first neurobiologic evidence that FM in RA may be linked to peripheral inflammation via pronociceptive patterns of brain connectivity. In patients with such "bottom-up" pain centralization, concomitant symptoms may partially respond to antiinflammatory treatments.

The German version of the Critical-Care Pain Observation Tool for critically ill adults : Aprospective validation study.

The implementation of the Critical-Care Pain Observation tool (CPOT) in intensive care units (ICU) has been associated with more frequent pain assessments, areduced number of complications, and improved administration of analgesics and sedatives. So far no German translation exists. Translating this tool into foreign languages requires further validation testing. The aim of this prospective observational validation study was to translate the original version of the CPOT according to scientific principles for translation and to establish the validity and reliability of the German translation of CPOT for critically ill adult patients. A total of 292 cardiac surgery patients from 2 ICUs of 2 German university teaching hospitals were included (114 patients at center1 and 178 patients at center2). Of the included patients 22.6% were female and 76.4% were male with amean age of 68.5 years ±9.3SD. Pain was evaluated with the CPOT, the Bhavioral Pain Scale (BPS) and with the Numeric Rating scale (NRS) at three time points (1.intubated + sedated, 2.intubated + awake, 3.extubated + awake) at rest and during nociceptive stimulus (positioning). Assessments were made separately by trained physicians and nursing staff. Good results for interrater reliability and internal consistency could be demonstrated (weighted Cohen's kappa of 0.73, Cronbach's coefficient alpha of 0.8). Spearman correlation between CPOT and NRS was moderate but significant. The receiver operating characteristic (ROC) analysis to obtain optimal thresholds of CPOT to detect pain revealed different results during rest and stimulus and in intubated and extubated patients. The validated German CPOT translation is areliable tool for pain assessment in cardiac ICU patients in the absence of patients' ability for self-reporting. The use of this German version of CPOT now allows abetter international comparability of corresponding data in future studies.

Delta-9-tetrahydrocannabinol reduces the performance in sensory delayed discrimination tasks. A pharmacological-fMRI study in healthy volunteers

BackgroundCannabis proofed to be effective in pain relief, but one major side effect is its influence on memory in humans. Therefore, the role of memory on central processing of nociceptive information was investigated in healthy volunteers. MethodsIn a placebo-controlled cross-over study including 22healthy subjects, the effect of 20mg oral Δ9-tetrahydrocannabinol (THC) on memory involving nociceptive sensations was studied, using a delayed stimulus discrimination task (DSDT). To control for nociceptive specificity, a similar DSDT-based study was performed in a subgroup of thirteen subjects, using visual stimuli. ResultsFor each nociceptive stimulus pair, the second stimulus was associated with stronger and more extended brain activations than the first stimulus. These differences disappeared after THC administration. The THC effects were mainly located in two clusters comprising the insula and inferior frontal cortex in the right hemisphere, and the caudate nucleus and putamen bilaterally. These cerebral effects were accompanied in the DSDT by a significant reduction of correct ratings from 41.61% to 37.05% after THC administration (rm-ANOVA interaction “drug” by “measurement”: F (1,21)=4.685, p=0.042). Rating performance was also reduced for the visual DSDT (69.87% to 54.35%; rm-ANOVA interaction of “drug” by “measurement”: F (1,12)=13.478, p=0.003) and reflected in a reduction of stimulus-related brain deactivations in the bilateral angular gyrus. ConclusionsResults suggest that part of the effect of THC on pain may be related to memory effects. THC reduced the performance in DSDT of nociceptive and visual stimuli, which was accompanied by significant effects on brain activations. However, a pain specificity of these effects cannot be deduced from the data presented.

Threat Memory Reminder Under Matrix Metalloproteinase 9 Inhibitor Doxycycline Globally Reduces Subsequent Memory Plasticity.

Associative memory can be rendered malleable by a reminder. Blocking the ensuing reconsolidation process is suggested as a therapeutic target for unwanted aversive memories. Matrix metalloproteinase-9 (MMP-9) is required for structural synapse remodeling involved in memory consolidation. Inhibiting MMP-9 with doxycycline is suggested to attenuate human threat conditioning. Here, we investigated whether MMP-9 inhibition also interferes with threat memory reconsolidation. Male and female human participants (N = 78) learned the association between two visual conditioned stimuli (CS+) and a 50% chance of an unconditioned nociceptive stimulus (US), and between CS− and the absence of US. On day 7, one CS+ was reminded without reinforcement 3.5 h after ingesting either 200 mg of doxycycline or placebo. On day 14, retention of CS memory was assessed under extinction by fear-potentiated startle. Contrary to our expectations, we observed a greater CS+/CS− difference in participants who were reminded under doxycycline compared with placebo. Participants who were reminded under placebo showed extinction learning during the retention test, which was not observed in the doxycycline group. There was no difference between the reminded and the nonreminded CS+ in either group. In contrast, during relearning after the retention test, the CS+/CS− difference was more pronounced in the placebo group than in the doxycycline group. To summarize, a single dose of doxycycline before threat memory reminder appeared to have no specific impact on reconsolidation, but to globally impair extinction learning, and threat relearning, beyond drug clearance.SIGNIFICANCE STATEMENT Matrix metalloproteinase-9 inhibition appears to attenuate memory consolidation. It could also be a target for blocking reconsolidation. Here, we test this hypothesis in human threat conditioning. We find that doxycycline has no specific impact on a reminded cue, but confers a global reduction in extinction learning and threat learning beyond the clearance of the drug. This may point toward a more long-lasting impact of doxycycline treatment on memory plasticity.

The influence of visual experience and cognitive goals on the spatial representations of nociceptive stimuli.

Localizing pain is crucial because it allows for detecting which part of the body is being hurt and identifying in its surrounding which stimulus is producing the damage. Nociceptive inputs should therefore be mapped according to somatotopic ("which limb is stimulated?") and spatiotopic representations ("where is the stimulated limb?"). Because the body posture constantly changes, the brain has to realign the different spatial representations, for instance when the arms are crossed with the left hand in the right space and vice versa, to adequately guide actions towards the threatening object. Such ability is thought to be dependent on past sensory experience and contextual factors. We compared performances of early blind and normally sighted participants during temporal order judgement tasks. Two nociceptive stimuli were applied, one on each hand, with the hands either uncrossed or crossed. Participants reported which stimulus they perceived as first presented, according to either its location on the body or the position of the stimulated hand, respectively, prioritizing anatomy or external space as task-relevant reference frame. Relative to the uncrossed posture, sighted participants' performances were decreased when the hands were crossed, whatever the instruction be. Early blind participants' performances were affected by crossing the hands during spatial instruction, but not during anatomical instruction. These results indicate that nociceptive stimuli are automatically coded according to both somatotopic and spatiotopic representations, but the integration of the different spatial reference frames depends on early visual experience and ongoing cognitive goals, illustrating the plasticity and the flexibility of the nociceptive system.

Effect of Different Concentrations of Propofol Used as a Sole Anesthetic on Pupillary Diameter: A Randomized Trial.

Pupillometry monitoring under general anesthesia is based on the assumption that pupillary diameter variations reflect the adequacy of the provided analgesia to the intensity of the nociceptive surgical stimulus. The accurate interpretation of pupillometric data requires establishing clearly what the expected baseline unstimulated pupillary diameter at each specific level of hypnosis is. Opioids decrease pupillary diameter in a dose-dependent fashion. In contrast, the effects of hypnotic drugs on pupillary diameter are not well known. Our aim was to describe the potential relationship between propofol predicted effect-site concentrations (Cets) ranging from 1 to 3 µg/mL and pupillary diameter. Patients were randomized to receive propofol by target-controlled infusion at a predicted Cet of 1, 2, or 3 µg/mL (groups P1, P2, and P3, respectively). Pupillary diameter measurements were performed after 10 minutes of steady-state propofol infusion at the randomized Cet. No stimulation was performed during the study. Heart rate and bispectral index (BIS) were continuously recorded. Forty patients were included: (13, 14, and 13 in groups P1, P2, and P3, respectively). Mean pupillary diameter was 5.7 mm (1 mm) in group P1, 4.8 mm (1.3 mm) in group P2, and 3.3 mm (0.8 mm) in group P3. Propofol had a dose-dependent effect on pupillary diameter (linear regression R = 0.45, P < .001). Pupillary diameter was positively correlated with the BIS (Spearman r = 0.75 [95% confidence interval (CI), 0.54 to -0.87] P < .001). From 1 to 3 µg/mL of predicted Cet, propofol has a dose-dependent effect on pupillary diameter. Within this concentrations range, there is a positive correlation between BIS and pupillary diameter. The subcortical effect of propofol on pupillary diameter is correlated to its effect on the cortex. Studies assessing pupillary diameter as a marker of the nociception-antinociception balance should be performed in patients with a standardized depth of hypnosis.

Parasympathetic Tone Activity Evaluation to Discriminate Ketorolac and Ketorolac/Tramadol Analgesia Level in Swine.

Evaluation of nociceptive-antinociceptive balance during general anesthesia is still challenging and routinely based on clinical criteria. Analgesic drug delivered may be optimized with parasympathetic tone activity (PTA) monitor. This study compares ketorolac and ketorolac/tramadol balance analgesia using a PTA monitor. Pain intensity response was assessed using a 0-100 numerical state scale (PTA) after nociceptive stimuli in pigs under stable sevoflurane anesthesia. Bispectral index, heart rate, noninvasive blood pressure, and respiratory parameters were also measured. Animals were divided into 3 groups: without analgesia, ketorolac, and ketorolac/tramadol. Mean values or mean areas under the curve (AUC) in selected time periods were compared over time and between groups through a mixed-model repeated measures analysis of variance and nonparametric Kruskal-Wallis tests, followed by Bonferroni or Dunn's multiple comparisons. It was observed a significant decrease in the PTA AUC mean value after application of the stimulus in animals treated without analgesia and only with ketorolac. The PTA AUC mean value in the control group was significantly lower than the corresponding mean in ketorolac group. The ketorolac/tramadol group showed the highest PTA AUC mean values, significantly different from those obtained for the other 2 groups, with no significant differences detected over time. Bispectral index means showed no statistically significant differences either over time periods or between different treatment groups. Heart rate showed only a statistically significant increase in AUC mean between without analgesia and ketorolac/tramadol group, in the time period after the stimulus application. Noninvasive blood pressure means showed no statistically significant differences over time and between treatment groups. This study shows that a low dose combination of ketorolac and tramadol is sufficient to block the pain responses induced with a needle holder in pigs 20 minutes after its administration. The PTA monitor was able to clearly recognize the analgesic level between treatments and may be used to optimize analgesic drug delivered.

Effects of Conditioned Pain Modulation on the Nociceptive Flexion Reflex in Healthy People: A Systematic Review.

The nociceptive flexion reflex (NFR) is a spinal reflex induced by painful stimuli resulting in a withdrawal response. Research has shown that the NFR is inhibited through endogenous pain inhibitory mechanisms, which can be assessed by conditioned pain modulation (CPM) paradigms. Although accumulating research suggests that the NFR can be affected by CPM, no clear overview of the current evidence exists. Therefore, the present review aimed at providing such a synthesis of the literature. In addition, the influence of personal factors on the CPM of the NFR was investigated. A systematic review was performed and reported following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Five electronic databases were searched to identify relevant articles. Retrieved articles were screened on eligibility using predefined inclusion criteria. Risk of bias was investigated according to the modified Newcastle-Ottawa Scale. Levels of evidence and strength of conclusion were assigned following the guidelines of the Dutch Institute for Healthcare Improvement. Forty articles were included. There is some evidence that CPM produced by thermal or mechanical stimuli induces inhibitory effects on the NFR. However, inconclusive evidence exists with regard to the effect of electrical conditioning stimuli. While several personal factors do not affect CPM of the NFR, increased cognitive interference is associated with reduced NFR inhibition. The present review demonstrates that certain types of nociceptive conditioning stimuli have the potential to depress, at the spinal level, nociceptive stimuli elicited from distant body regions. Although CPM of the NFR seems to be robust to the influence of several personal factors, it can be affected by cognitive influences.

Efficacy of the Parasympathetic Tone Activity monitor to assess nociception in healthy dogs anaesthetized with propofol and sevoflurane

ObjectiveTo compare a Parasympathetic Tone Activity (PTA) monitor with cardiovascular changes in invasive mean arterial pressure (IMAP) and heart rate (HR) when evaluating the response to nociceptive stimuli in anaesthetized dogs. Study designProspective experimental study. AnimalsA group of nine (seven male and two female) adult Beagle dogs weighing 13.4 ± 1.5 kg (mean ± standard deviation). MethodsAnaesthesia was induced with propofol and maintained with sevoflurane in oxygen. Electrical stimuli of different nociceptive intensities were applied for 30 seconds. Stimuli were classified in each patient according to the response obtained (relevant change ≥ 20%) as low (no response), medium (PTA only) or high (PTA and IMAP/HR). Immediate and averaged values of PTA, IMAP and HR were recorded every second from 60 seconds before to 120 seconds after application of the nociceptive stimulus. Time to nociceptive response and peak response were evaluated with analysis of variance and t test. ResultsImmediate PTA baseline values did not differ significantly before application of the low, medium and high stimuli (73 ± 15, p = 0.966). Immediate PTA response was observed with the medium stimulus at 33 ± 7 seconds with a maximum decrease of 57 ± 13% at 69 ± 5 seconds. With the high stimulus, the immediate PTA response was of a similar magnitude to the medium stimulus with a response at 28 ± 7 seconds (p = 0.221) and a maximum decrease of 68 ± 15% (p = 0.115) at 72 ± 7 seconds (p = 0.436). The cardiovascular change occurred (22 ± 8 seconds) prior to the immediate PTA response (p = 0.032). Conclusions and clinical relevanceThe PTA monitor detected nociceptive stimuli at lower intensities than those eliciting cardiovascular changes. However, nociceptive stimuli of higher intensities provoked cardiovascular changes that occurred before a PTA response was observed.

Impaired Motor Learning Following a Pain Episode in Intact Rats.

Motor learning and pain are important factors influencing rehabilitation. Despite being mostly studied independently from each other, important interactions exist between them in the context of spinal cord injury, whether to the spinal cord or the body. Ongoing or recent past episodes of nociceptive activity can prevent motor learning in spinalized rats. In intact animals, it has been proposed that supraspinal activity could counter the repressive effect of nociception on motor system plasticity, but this has not yet been verified in behavioral conditions. The aim of this study was to test whether a recent episode of nociception affects subsequent motor learning in intact animals. We trained rodents to walk on a custom-made horizontal ladder. After initial training, the rats underwent a week-long rest, during which they were randomly assigned to a control group, or one out of two pain conditions. Nociceptive stimuli of different durations were induced through capsaicin or Complete Freund's Adjuvant injections and timed so that the mechanical hypersensitivity had entirely subsided by the end of the resting period. Training then resumed on a modified version of the horizontal ladder. We evaluated the animals' ability to adapt to the modified task by measuring their transit time and paw misplacements over 4 days. Our results show that prior pain episodes do affect motor learning in neurologically intact rats. Motor learning deficits also seem to be influenced by the duration of the pain episode. Rats receiving a subcutaneous injection of capsaicin displayed immediate signs of mechanical hypersensitivity, which subsided rapidly. Nonetheless, they still showed learning deficits 24 h after injection. Rats who received a Complete Freund's Adjuvant injection displayed mechanical hypersensitivity for up to 7 days during the resting period. When trained on the modified ladder task upon returning to normal sensitivity levels, these rats exhibited more prolonged motor learning deficits, extending over 3 days. Our results suggest that prior pain episodes can negatively influence motor learning, and that the duration of the impairment relates to the duration of the pain episode. Our results highlight the importance of addressing pain together with motor training after injury.

Sleep restriction does not potentiate nocebo‐induced changes in pain and cortical potentials

The increased pain sensitivity following reduced sleep may be related to changes in cortical processing of nociceptive stimuli. Expectations shape pain perception and can inhibit (placebo) or enhance (nocebo) pain. Sleep restriction appears to enhance placebo responses; however, whether sleep restriction also affects nocebo responses remains unknown. The aim of the present study was to determine whether sleep restriction facilitates nocebo-induced changes in pain and pain-evoked cortical potentials. In an experimental study with a crossover design, the sensitivity to electrically induced pain was determined in 53 nurses under two sleep conditions, after habitual sleep and after two consecutive nights at work. Nocebo was induced by conditioning one-third of the pain stimuli. Pain-elicited cortical event-related potentials were recorded by electroencephalography (EEG). Data were analysed both in the time domain (N2P2 amplitude) and in the time-frequency domain (ERP magnitude). Sleepiness and vigilance were also assessed. Both nocebo alone and sleep restriction alone increased the sensitivity to electrically induced pain. However, no interaction effect was found. Moreover, the magnitude of the pain-elicited responses increased after sleep restriction and decreased after nocebo expectation, suggesting that nocebo is probably not an underlying mechanism for the commonly observed hyperalgesia induced by sleep restriction. The present work addresses whether sleep restriction, known to increase the sensitivity of the pain system, facilitates nocebo-induced hyperalgesia. Our findings suggest that this is not the case, indicating that the increased sensitivity of the pain system following nocebo and sleep restriction are mediated by different cortical mechanisms.