Nociceptive Withdrawal Reflex Threshold Research Articles

The effect of methylphenidate on anaesthesia recovery: An experimental study in pigs.

Due to the lack of specific antagonists for general anaesthetics, the pharmacological stimulation of the arousal pathways might contribute to reduce recovery time. We aimed at assessing the effect of methylphenidate on physiological parameters, nociceptive withdrawal reflex thresholds, electroencephalographic variables and time of reappearance of reflexes in pigs undergoing propofol anaesthesia. Two experiments have been performed. Five (experiment 1) and sixteen (experiment 2) healthy juvenile pigs were anaesthetised with propofol. In experiment 1, saline, methylphenidate 10 mg/kg or methylphenidate 20 mg/kg was administered intravenously at the end of propofol administration, using a cross-over design. In experiment 2, saline (n = 8) or methylphenidate 20 mg/kg (n = 8) was administered immediately after extubation. In both experiments, physiological parameters, nociceptive withdrawal reflex thresholds, electroencephalographic variables and time of reappearance of reflexes were assessed. Comparison among groups was performed using either the two-way repeated measures ANOVA followed by Bonferroni-Test or the t-test in case of parametric data, and either the Kruskal-Wallis test or the Mann-Whitney Rank Sum test in case of non-parametric data. A p value < 0.05 was considered statistically significant. No clinically relevant changes were observed in both experiments for physiological parameters, nociceptive withdrawal reflex thresholds and electroencephalographic variables. Methylphenidate does not shorten or modify anaesthesia recovery in pigs, when the sole propofol is administered.

How Is the Nociceptive Withdrawal Reflex Influenced by Increasing Doses of Propofol in Pigs?

The nociceptive withdrawal reflex (NWR) is a physiological, polysynaptic spinal reflex occurring in response to noxious stimulations. Continuous NWR threshold (NWRt) tracking has been shown to be possibly useful in the depth of anesthesia assessment. The primary aim of this study was to describe how propofol modulates the NWRt over time in pigs. Five juvenile pigs (anesthetized three times) were included. An intravenous (IV) infusion of propofol (20 mg/kg/h) was started, and boli were administered to effect until intubation. Afterwards, the infusion was increased every ten minutes by 6 mg/kg/h, together with an IV bolus of 0.5 mg/kg, until reaching an electroencephalographic suppression ratio (SR) of between 10% and 30%. The NWRt was continuously monitored. For data analysis, the time span between 15 min following intubation and the end of propofol infusion was considered. Individual durations of propofol administration were divided into five equal time intervals for each pig (TI1-TI5). A linear regression between NWRt and TI was performed for each pig. Moreover, the baseline NWRt and slopes of the linear regression (b1) were compared among days using a Friedman Repeated Measures Analysis of Variance on Ranks. The NWRt always increased with the propofol dose (b1 = 4.71 ± 3.23; mean ± standard deviation). No significant differences were found between the baseline NWRt and the b1 values. Our results suggest that the NWRt may complement the depth of anesthesia assessment in pigs receiving propofol.

Effects of transcutaneous auricular vagus nerve stimulation at left cymba concha on experimental pain as assessed with the nociceptive withdrawal reflex, and correlation with parasympathetic activity.

The aim of this study was to clarify the effects of transcutaneous auricular vagus nerve stimulation (taVNS) to the left cymba concha on the pain perception using nociceptive withdrawal reflex (NWR), which is known to be associated with chronic pain, and to investigate whether there is a relationship between taVNS-induced suppression of the NWR and parasympathetic activation. We applied either 3.0mA, 100 Hz taVNS for 120 s on the left cymba concha (taVNS condition) or the left earlobe (Sham condition) for 20 healthy adults. NWR threshold was measured before (Baseline), immediately after (Post 0), 10min (Post 10) and 30 min after (Post 30) stimulation. The NWR threshold was obtained from biceps femoris muscle by applying electrical stimulation to the sural nerve. During taVNS, electrocardiogram was recorded, and changes in autonomic nervous activity measured by heart rate variability (HRV) were analyzed. We found that the NWR thresholds at Post 10 and Post 30 increased compared with baseline in the taVNS group (10min after: p = .008, 30 min after: p = .008). In addition, increased parasympathetic activity by taVNS correlated with a greater increase in NWR threshold at Post 10 and Post 30 (Post 10: p = .003; Post 30: p = .001). The present results of this single-blinded study demonstrate the pain-suppressing effect of taVNS on NWR threshold and suggest that the degree of parasympathetic activation during taVNS may predict the pain-suppressing effect of taVNS after its application.

Nociceptive withdrawal reflexes of the trunk muscles in chronic low back pain.

Individuals with chronic low back pain (CLBP) move their spine differently. Changes in brain motor areas have been observed and suggested as a mechanism underlying spine movement alteration. Nociceptive withdrawal reflex (NWR) might be used to test spinal networks involved in trunk protection and to highlight reorganization. This study aimed to determine whether the organization and excitability of the trunk NWR are modified in CLBP. We hypothesized that individuals with CLBP would have modified NWR patterns and lower NWR thresholds. Noxious electrical stimuli were delivered over S1, L3 and T12, and the 8th Rib to elicit NWR in 12 individuals with and 13 individuals without CLBP. EMG amplitude and occurrence of lumbar multifidus (LM), thoracic erector spinae, rectus abdominus, obliquus internus and obliquus externus motor responses were recorded using surface electrodes. Two different patterns of responses to noxious stimuli were identified in CLBP compared to controls: (i) abdominal muscle NWR responses were generally more frequent following 8th rib stimulation and (ii) occurrence of erector spinae NWR was less frequent. In addition, we observed a subgroup of participants with very high NWR threshold in conjunction with the larger abdominal muscle responses. These results suggest sensitization of NWR is not present in all individuals with CLBP, and a modified organization in the spinal networks controlling the trunk muscles that might explain some changes in spine motor control observed in CLBP.

Comparison of Threshold and Tolerance Nociceptive Withdrawal Reflexes in Horses.

Simple SummaryNociception is the physiological basis of the complex experience of pain. An established model for its quantification in equine studies is based on the nociceptive withdrawal reflex evoked by electrical stimulation of a sensory nerve. The reflex is recorded via electromyography and it is common to determine the threshold at which a nociceptive-specific reflex activity can be observed. In the present study, the classical methodology was expanded for a deeper understanding of the physiology of nociceptive reflexes in horses. First, for each individual horse, a threshold was determined as the minimal stimulation intensity able to evoke a nociceptive withdrawal reflex. Second, the stimulation intensity was stepwise increased up to tolerance, which was defined as the stimulus that is able to elicit the maximal tolerable behavioral reaction. The characteristics of the reflex activity on the electromyographic records were compared for threshold and tolerance stimulation intensities. At tolerance, the reflex became faster and wider than at threshold, indicating that either a spinal summation mechanism or the recruitment of faster sensory fibers occurs in response to high-intensity noxious stimuli. A novel endpoint (i.e., tolerance) can now be considered when applying the nociceptive withdrawal reflex model in equine studies.The nociceptive withdrawal reflex (NWR) is used to investigate nociception in horses. The NWR threshold is a classical model endpoint. The aims of this study were to determine NWR tolerance and to compare threshold and tolerance reflexes in horses. In 12 horses, the NWR was evoked through electrical stimulation of the digital nerve and recorded via electromyography from the deltoid. Behavioral reactions were scored from 0 to 5 (tolerance). First, the individual NWR threshold was defined, then stimulation intensity was increased to tolerance. The median NWR threshold was 7.0 mA, whereas NWR tolerance was 10.7 mA. Upon visual inspection of the records, two main reflex components R1 (median latency 44 ms) and R2 (median latency 81 ms) were identified at threshold. Increasing stimulation intensity to tolerance led to a significant increase in the amplitude and duration of R1 and R2, whereas their latency decreased. At tolerance, a single burst of early, high-amplitude reflex activity, with a median latency of 39 ms, was detected in 15 out of 23 stimulations (65%). The results of this study suggest that (1) it is feasible to determine NWR tolerance in horses and (2) high-intensity stimuli initiate ultrafast bursts of reflex activity, which is well known in practice and has now been quantified using the NWR model.

Exploring the effect of capsaicin-induced central sensitization on the upper limb nociceptive withdrawal reflex threshold.

The nociceptive withdrawal reflex (NWR) threshold is commonly employed in the lower limb to assess clinical and experimentally induced pain. However, no studies to date have investigated changes in spinal nociception in the upper limb, via the NWR threshold, following experimentally induced central sensitization (CS). We tested the hypothesis that experimentally induced CS of the C5-C6 spinal segment significantly reduces NWR thresholds in muscles of the upper limb. Upper limb NWR thresholds from 20 young, healthy adults were assessed by applying noxious electrical stimuli to the right index finger and recording muscle activity from the biceps brachii (BI), triceps brachii (TRI), flexor carpi ulnaris (WF), and extensor carpi radialis longus (WE) muscles via surface electromyography. Topical cream (either 0.075% capsaicin, or control) was applied to the C5-C6 dermatome of the lateral forearm (50 cm2). NWR thresholds were compared at baseline, and four 10-min intervals after topical application. WF muscle NWR thresholds were significantly reduced in the capsaicin session compared to control, while TRI muscle NWR thresholds were significantly reduced 40min after capsaicin application only (p < 0.05). There were no significant differences for BI or WE muscle NWR thresholds. We observed poor to moderate test-retest reliability for all upper limb NWR thresholds, a key contributor to the selective reduction in NWR thresholds among muscles. Accordingly, while our findings demonstrate some comparability to previously reported lower limb NWR studies, we concurrently report limitations of the upper limb NWR technique. Further exploration of optimal parameters for upper limb NWR acquisition is needed.

Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally induced migraine attacks.

Migraine pathophysiology has been suggested to include dysregulation of the endocannabinoid system (ES). We simultaneously evaluated plasma anandamide (AEA) and palmitoylethanolamide (PEA) levels and spinal sensitization in a validated human model of migraine based on systemic nitroglycerin (NTG) administration. Twenty-four subjects with episodic migraine (MIG) and 19 healthy controls (HC) underwent blood sampling and investigation of nociceptive withdrawal reflex thresholds (RTh: single-stimulus threshold; TST: temporal summation threshold) before and 30 (T30), 60 (T60), and 120 (T120) minutes after sublingual NTG administration (0.9 mg). At baseline, the MIG and HC groups were comparable for plasma AEA (P = 0.822) and PEA (P = 0.182) levels, and for RTh (P = 0.142) and TST values (P = 0.150). Anandamide levels increased after NTG administration (P = 0.022) in both groups, without differences between them (P = 0.779). By contrast, after NTG administration, PEA levels increased in the MIG group at T120 (P = 0.004), while remaining stable in the HC group. Nitroglycerin administration induced central sensitization in the MIG group, which was recorded as reductions in RTh (P = 0.046) at T30 and T120, and in TST (P = 0.001) at all time points. In the HC group, we observed increases in RTh (P = 0.001) and TST (P = 0.008), which suggest the occurrence of habituation. We found no significant correlations between the ES and neurophysiological parameters. Our findings suggest a role for PEA in the ictal phase of episodic migraine. The ES does not seem to be directly involved in the modulation of NTG-induced central sensitization, which suggests that the observed PEA increase and spinal sensitization are parallel, probably unrelated, phenomena.

Antinociceptive effects of levomethadone in standing horses sedated with romifidine

ObjectiveTo evaluate the antinociceptive effect of a bolus of intravenous levomethadone administered to horses during romifidine constant rate infusion (CRI). Study designProspective, randomized, masked, crossover experimental study. AnimalsA group of eight adult Warmblood horses (seven geldings, one mare) aged 6.6 ± 4.4 years, weighing 548 ± 52 kg [mean ± standard deviation (SD)]. MethodsLevomethadone 0.1 mg kg–1 or an equivalent volume of saline (control) was administered intravenously to standing horses 60 minutes after starting a romifidine CRI. Blood samples to quantify romifidine and levomethadone plasma concentrations by capillary electrophoresis were collected up to 150 minutes after levomethadone administration. The nociceptive withdrawal reflex threshold (NWRT) was determined continuously using an automated threshold tracking device. Sedation and cardiopulmonary variables were assessed at regular intervals. A pharmacokinetic-pharmacodynamic (PK-PD) model was elaborated. Data are presented as mean ± SD or median (interquartile range, 25%–75%) where appropriate. Differences between groups were considered statistically significant for p < 0.05. ResultsHorses exhibited higher NWRTs after levomethadone administration than after saline (123 ± 9% versus 101 ± 9% relative to baseline, p < 0.05). The PK-PD model identified a contribution of levomethadone to the NWRT increase. Effect size was variable among individuals. No adverse reactions to levomethadone administration were observed. A slight effect of levomethadone on sedation scores was evident for the 60 minutes following its administration. Conclusions and Clinical RelevanceA single injection of levomethadone has the potential to increase the NWRT during romifidine CRI in horses and can be administered in combination with α2-adrencoceptor agonists to enhance antinociception in horses. However, individual variation is marked.

Spinal spatial integration of nociception and its functional role assessed via the nociceptive withdrawal reflex and psychophysical measures in healthy humans.

Animal studies have previously shown that deep dorsal horn neurons play a role in the processing of spatial characteristics of nociceptive information in mammals. Human studies have supported the role of the spinal neurons; however, the mechanisms involved, and its significance, remain to be clarified. The aim of this study was to investigate spatial aspects of the spinal integration of concurrent nociceptive electrical stimuli in healthy humans using the Nociceptive Withdrawal Reflex (NWR) as an objective indication of spinal nociceptive processing. Fifteen healthy volunteers participated in the study. Electrical stimuli were delivered, using five electrodes located across the sole of the foot in a mediolateral disposition, as a single or double simultaneous stimuli with varying Inter‐Electrode Distances (IEDs). The stimulation intensity was set at 1.5× NWR threshold (TA muscle). The size of the NWR was quantified in the 60–180 ms poststimulus window as a primary outcome measure. Psychophysical measures were secondary outcomes. Single stimulation elicited significantly smaller NWRs and perceived intensity than double stimulation (p < .01), suggesting the presence of spatial summation occurring within the spinal processing. During double stimulation, increasing the inter‐electrode distance produced significantly smaller NWR sizes (p < .05) but larger pain intensity ratings (p < .05). By the NWR, spatial summation was shown to affect the nociceptive processing within the spinal cord. The inhibited motor response obtained when simultaneously stimulating the medial and lateral side of the sole of the foot suggests the presence of an inhibitory mechanism with a functional, behaviorally oriented function.

Effect of Medetomidine, Dexmedetomidine, and Their Reversal with Atipamezole on the Nociceptive Withdrawal Reflex in Beagles.

Simple SummaryMedetomidine, an alpha-2 agonist routinely used to provide sedation and pain relief in dogs, is a mixture of dexmedetomidine and levomedetomidine in equal proportions. Dexmedetomidine, considered to be the only active component in the mixture, is also marketed alone. Sedation caused by both formulations can be reversed using atipamezole, which shortens recovery. Dexmedetomidine provides analgesic effects similar to medetomidine, but it remains unclear at which dose and whether the analgesic effects of medetomidine or dexmedetomidine disappear once atipamezole is injected. The present trial aimed at elucidating these uncertainties using the nociceptive withdrawal reflex model. This model allows for quantification of analgesia by measuring specific activity from muscles involved in limb withdrawal in response to mild electrical stimulation. In eight beagles, the model was applied to compare the extent of pain relief provided by medetomidine and dexmedetomidine and to investigate whether complete reversal occurs after the administration of atipamezole. No difference in analgesic efficacy was identified between the two formulations. Both sedation and pain relief terminated rapidly when atipamezole was administered. These findings indicate that medetomidine and dexmedetomidine provide comparable levels of pain relief and that additional analgesics may be necessary when atipamezole is administered to dogs experiencing pain.The objectives were: (1) to compare the antinociceptive activity of dexmedetomidine and medetomidine, and (2) to investigate its modulation by atipamezole. This prospective, randomized, blinded experimental trial was carried out on eight beagles. During the first session, dogs received either medetomidine (MED) (0.02 mg kg−1 intravenously (IV)] or dexmedetomidine (DEX) [0.01 mg kg−1 IV), followed by either atipamezole (ATI) (0.1 mg kg−1) or an equivalent volume of saline (SAL) administered intramuscularly 45 min later. The opposite treatments were administered in a second session 10–14 days later. The nociceptive withdrawal reflex (NWR) threshold was determined using a continuous tracking approach. Sedation was scored (0 to 21) every 10 min. Both drugs (MED and DEX) increased the NWR thresholds significantly up to 5.0 (3.7–5.9) and 4.4 (3.9–4.8) times the baseline (p = 0.547), at seven (3–11) and six (4–9) minutes (p = 0.938), respectively. Sedation scores were not different between MED and DEX during the first 45 min (15 (12–17), p = 0.67). Atipamezole antagonized sedation within 25 (15–25) minutes (p = 0.008) and antinociception within five (3–6) minutes (p = 0.008). Following atipamezole, additional analgesics may be needed to maintain pain relief.

Automated Nociceptive Withdrawal Reflex Measurements Reveal Normal Reflex Thresholds and Augmented Pain Ratings in Patients with Fibromyalgia.

The nociceptive withdrawal reflex (NWR) is used to probe spinal cord excitability in chronic pain states. Here, we used an automated and unbiased procedure for determining the NWR threshold and compared the reflex thresholds and corresponding pain ratings in a well-characterized cohort of fibromyalgia (n = 29) and matched healthy controls (n = 21). Surface electrical stimuli were delivered to the foot in a stepwise incremental and decremental manner. The surface electromyographic activity was recorded from the ipsilateral tibialis anterior muscle. Fibromyalgia patients reported significantly higher scores for psychological distress and pain-related disability and a significantly lower score for perceived state of health compared to the matched controls. The subjective pain ratings were significantly higher in patients. The NWR thresholds were similar to the controls. In the patients, but not in controls, the NWR thresholds and subjective pain ratings were significantly correlated. Our results showed an increased subjective pain sensitivity in fibromyalgia, but we found no evidence for spinal sensitization based on the reflex measures.

Long term reliability of nociceptive withdrawal reflex thresholds

BackgroundThe nociceptive withdrawal reflex (NWR) is a polysynaptic spinal reflex protecting the body from harmful stimuli. Two different methods to assess its’ threshold (NWR-T) have been part of clinical trials concerning the evaluation of the nociceptive system in the human body. NWR-T’s are gathered by stimulation at the sole of the foot and over the sural pathway. Consequently, EMG analyzes the muscle activity over the biceps femoris and tibialis anterior muscle. Past studies favor stimulation at the sole of the foot. New methodThe two methods were compared concerning retest-reliability and subjective pain ratings. The retest-reliability was tested over a period of 21 days using an up-down staircase method. Reliability was evaluated with a Bland Altman agreement analysis. Subjective pain ratings were evaluated with a numeric rating scale (NRS). ResultsNWR-T assessment was successful for all subjects. The EMG muscle activity had larger reflex amplitudes for measurements of the tibialis anterior muscle. NWR-T values showed greater variability than NRS values. Comparison with existing methodThe retest-reliability over a period of 21 days showed stable NWR-T results for both stimulation sites, but superior reliability was gathered with stimulation at the sole of the foot. Subjects rated stimulation over the sural pathway as more painful. ConclusionsThe NWR-T upholds reliable measurements over a longer period of time and seems to be a stable measure for pain condition. Reliability estimations, EMG recordings, and subject’s rating show stimulation at the sole of the foot could be the better choice.

Electrophysiological characterisation of central sensitisation in canine spontaneous osteoarthritis.

In man, central sensitisation (CS) contributes to the pain of osteoarthritis (OA). Dogs with spontaneous OA may also exhibit CS. Electrophysiological reflex measurements are more objective than behavioural assessments and can be used to evaluate CS in preclinical and clinical studies. It was hypothesised that dogs suffering from OA would exhibit electrophysiological characteristics indicative of CS, associated with reduced diffuse noxious inhibitory controls (DNICs). One hundred and seventeen client-owned dogs were recruited to the study. Hind limb nociceptive withdrawal reflex thresholds, stimulus response, and temporal summation characteristics were recorded, during alfaxalone anaesthesia, from 46 OA dogs, 29 OA dogs receiving nonsteroidal anti-inflammatory drugs (OANSAIDs), and 27 breed- and weight-matched control dogs. Efficacy of DNIC was evaluated in 12 control and 11 of the OA dogs, by application of a mechanical conditioning stimulus to the contralateral forelimb. Nociceptive withdrawal reflex thresholds were higher in OA compared with control dogs (P = 0.02). Stimulus response characteristics demonstrated an augmented response in OANSAID dogs compared with OA (P < 0.001) and control (P < 0.001) dogs. Temporal summation demonstrated exaggerated C-fibre-mediated responses in both OA (P < 0.001) and OANSAID (P = 0.005) groups, compared with control animals. Conditioning stimulus application resulted in inhibition of test reflex responses in both OA and control animals (P < 0.001); control animals demonstrated greater inhibition compared with OA (P = 0.0499). These data provide evidence of neurophysiological changes consistent with CS in dogs with spontaneous OA and demonstrate that canine OA is associated with reduced DNIC.

Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity.

See Dickenson (doi:10.1093/brain/awx334) for a scientific commentary on this article.Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss-of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans.

Modulation of nociceptive threshold by combined hormonal contraceptives in women with oestrogen-withdrawal migraine attacks: a pilot study

BackgroundMenstrually-related headache and headaches associated with oestrogen withdrawal are common conditions, whose pathophysiology has not been completely elucidated. In this study we evaluated the influence of combined hormonal contraceptives (CHC) on pain threshold in women presenting migraine attacks during hormone-free interval.FindingsEleven women with migraine attacks recurring exclusively during the oestrogen-withdrawal period were studied with the nociceptive flexion reflex, a neurophysiological assessment of the pain control systems, during the third week of active treatment and during the hormone-free interval.During the hormone-free interval, nociceptive withdrawal reflex threshold was significantly lower (12.8 ± 8.0 mA) as compared to the third week of hormonal treatment (15.6 ± 6.6 mA) (p = 0.02). No change was observed in the pain perceived and in the temporal summation.ConclusionsOestrogen withdrawal may mediate an increased sensitivity to somatosensory stimuli in women with migraine attacks recurring during the hormone-free interval.

The model of the Nociceptive Withdrawal Reflex in horses

In equine pain research, the Nociceptive Withdrawal Reflex (NWR) model has been proposed as an alternative to classical thermal, mechanical and electrical models to investigate the physiology of nociception. This model does not only allow a more reliable definition of the nociceptive threshold through neurophysiological characterization of the elicited response , but also consents plotting a stimulus-response curve as well as the evaluation of temporal summation mechanisms. Aim of this report is to summarize the experience and results obtained using the NWR model in horses over the last 15 years, firstly with the purpose of describing its physiological characteristics and secondly with the aim of evaluating its pharmacological modulation through analgesic and anaesthetic compounds. The NWR can be elicited in horses through electrical transcutaneous stimulation of a peripheral sensory nerve and is recorded through electromyographic electrodes from the muscles involved in the withdrawal reaction. As the non-nociceptive fibres have lower threshold to electrical stimuli than the nociceptive one, it is impossible to differentiate between the two groups on the stimulus side. So, the only guidance to assess the quality of the stimulus and the recruitment of nociceptive afferents should rely on the characteristics of the electromyographic response, most of all on the timing of its various components. A reflex response can be considered to be a true NWR only if it appears within a time epoch compatible with the conduction velocity of the Aδ fibers. Furthermore a clearly recognizable EMG burst in the epoch of interest has to be accompanied by a consistent aversive behavioural reaction, thus allowing the definition of a reliable NWR threshold. Responses to stimulation intensities below and above thresholds can be quantified to draw a stimulus response curve. Furthermore, through repeated stimulation at subthreshold intensities, it is possible to elicit the phenomenon of temporal summation, considered to be the early phase of the wind up phenomenon and of relevant interest to study central integrative mechanisms of pain processing. Alpha-2 agonists, opioids, systemic lidocaine, ketamine and inhalation anaesthetics have been investigated using the NWR model in horses. Drug-specific modulation of NWR threshold, stimulus-response curves and temporal summation are summarized for each tested compound.

Pain hypersensitivity and spinal nociceptive hypersensitivity in chronic pain: prevalence and associated factors.

Hypersensitivity of pain pathways is considered a relevant determinant of symptoms in chronic pain patients, but data on its prevalence are very limited. To our knowledge, no data on the prevalence of spinal nociceptive hypersensitivity are available. We studied the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity in 961 consecutive patients with various chronic pain conditions. Pain threshold and nociceptive withdrawal reflex threshold to electrical stimulation were used to assess pain hypersensitivity and spinal nociceptive hypersensitivity, respectively. Using 10th percentile cutoff of previously determined reference values, the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity (95% confidence interval) was 71.2 (68.3-74.0) and 80.0 (77.0-82.6), respectively. As a secondary aim, we analyzed demographic, psychosocial, and clinical characteristics as factors potentially associated with pain hypersensitivity and spinal nociceptive hypersensitivity using logistic regression models. Both hypersensitivity parameters were unaffected by most factors analyzed. Depression, catastrophizing, pain-related sleep interference, and average pain intensity were significantly associated with hypersensitivity. However, none of them was significant for both unadjusted and adjusted analyses. Furthermore, the odds ratios were very low, indicating modest quantitative impact. To our knowledge, this is the largest prevalence study on central hypersensitivity and the first one on the prevalence of spinal nociceptive hypersensitivity in chronic pain patients. The results revealed an impressively high prevalence, supporting a high clinical relevance of this phenomenon. Electrical pain thresholds and nociceptive withdrawal reflex explore aspects of pain processing that are mostly independent of sociodemographic, psychological, and clinical pain-related characteristics.

Ipsilateral resistance exercise prevents exercise-induced central sensitization in the contralateral limb: a randomized controlled trial.

This study aimed to investigate the hypothesis that a repeated bout of eccentric exercise (ECC2) would result in smaller increase in the sensitivity of spinal nociceptive system, and smaller decrease in the local muscle blood oxygenation response in both the ipsilateral and the contralateral tibialis anterior muscle (TA) when compared with the initial bout (ECC1). It was hypothesized that the magnitude of the repeated bout effect (RBE) would be greater for the ipsilateral side than the contralateral side. Twenty-six healthy young men performed two bouts of high-intensity eccentric exercise of TA separated by 2 weeks. Half of the participants used the same leg for both bouts (IPSI) and the other half used the contralateral leg for ECC2 (CONTRA). Nociceptive withdrawal reflex threshold (NWRT) and local muscle blood oxygenation were assessed for the exercised TA muscle before, immediately after, and one day after exercise. Significant decreases in NWRT and muscle oxygenation were observed after ECC1 (p<0.05), but NWRT did not change after ECC2 in both groups. Smaller decreases in muscle oxygenation were observed after ECC2 than ECC1 in both groups with a similar magnitude of the difference between bouts, but an increase in muscle oxygen re-perfusion before ECC2 was only observed in the IPSI group. These results suggest that contralateral RBE was associated with spinal facilitation of the neuronal pathways situated at a homologous innervation level, and it is unlikely that oxygen re-perfusion improvement plays a major role in the contralateral RBE.

Reliable estimation of nociceptive withdrawal reflex thresholds

BackgroundAssessment of the nociceptive withdrawal reflex (NWR) is frequently applied to probe the excitability level of the spinal nociceptive circuitry. In humans, the NWR threshold (NWR-T) is often estimated by applying electrical stimulation over the sural nerve at the lateral malleolus. Such stimulation may be associated with substantial pain and discomfort rendering completion of the assessment infeasible. New methodAs an alternative to sural nerve stimulation, NWR-Ts were also estimated by electrical stimulation at the arch of the foot. Failure-rates and test–retest reliability of these two procedures were evaluated. A fully-automated interleaved up-down staircase procedure was used to estimate the NWR-T for both stimulation sites. NWRs were detected from EMG measured over the biceps femoris and tibialis anterior muscles, respectively. A total of three repeated measures were performed in two different sessions to evaluate the test–retest reliability of the two methods using Bland–Altman agreement analysis. ResultsThe failure rate of NWR-T estimation based on electrical stimulation of the sural nerve (29%) was substantially higher than when the NWR was elicited by stimulation at the arch of the foot (5%). Comparison with existing methodThe analysis of test–retest reliability indicated that the two methods for NWR-T estimation were equally reliable for within-session comparisons, but stimulation at the arch of the foot enabled NWR-T estimation with superior between-session reliability ConclusionsThese results support a paradigm shift within NWR-T estimation favoring stimulation at the arch of the foot.

Antinociceptive effect of buprenorphine and evaluation of the nociceptive withdrawal reflex in foals

ObjectiveTo elicit and evaluate the NWR (nociceptive withdrawal reflex) in 2 and 11 day old foals, to investigate if buprenorphine causes antinociception and determine if the NWR response changes with increasing age. The effect of buprenorphine on behaviour was also evaluated. Study designProspective, experimental cross-over trial. AnimalsNine Norwegian Fjord research foals. MethodsBuprenorphine, 10 μg kg−1 was administered intramuscularly (IM) to the same foal at 2 days and at 11 days of age. The NWR and the effect of buprenorphine were evaluated by electromyograms recorded from the left deltoid muscle following electrical stimulation of the left lateral palmar nerve at the level of the pastern. Mentation, locomotor activity and respiratory rate were recorded before and after buprenorphine administration. ResultsWe were able to evoke the NWR and temporal summation in foals using this model. Buprenorphine decreased the root mean square amplitude following single electrical stimulation (p < 0.001) in both age groups, and increased the NWR threshold following single electrical stimulation in 2 day old foals (p = 0.0012). Repeated electrical stimulation at 2 Hz was more effective to elicit temporal summation compared to 5 Hz (p < 0.001). No effect of age upon the NWR threshold was found (p = 0.34). Sedation when left undisturbed (11 occasions), increased locomotor activity when handled (9 occasions) and tachypnea (13 occasions) were common side-effects of buprenorphine. Conclusion and clinical relevanceThese findings indicate that buprenorphine has antinociceptive effect in foals. Opioid side effects often recognized in adult horses also occur in foals.