Noxious Cold Stimulation Research Articles

Towards a central origin of nociceptive hypersensitivity in adult rats after a neonatal maternal separation.

Early life adversities influence a nervous system still in development with long-term consequences for later life. These include nociceptive circuit alterations critical to shape an adaptive pain response to protect the organism from potential damage. Adult rats with a history of neonatal maternal separation (NMS) display visceral and somatic nociceptive hypersensitivity and inefficient analgesic responses to stress. In this study, we have characterized the consequences of NMS on wide dynamic range neurons (WDR) in the spinal cord of anaesthetized adult rats during the nociceptive processing of hot and cold noxious information. We found that WDR neurons of NMS rats display an excessive coding of mechanical and thermal information applied at the rat's hindpaws. This nicely explains the hypernociceptive behaviours seen after noxious mechanical, cold and hot peripheral stimulation. A peripheral change in the expression of molecular transducers for these stimuli (i.e., TRPV1, TRPM8 and TRPA1) does not seem to account for this general hyperexcitability. Instead, a decreased chloride-mediated inhibitory tone on WDR neurons may play a role as indicated by the abnormal elevation of the type 1 Na-K-Cl cotransporter transcripts. Altogether, we propose that long-term consequences of NMS are associated with reduced spinal cord inhibition favouring the expression of pain hypersensitivity. We cannot exclude that this phenomenon is also present at supraspinal sites, as other NMS-associated symptoms include excessive anxiety and impaired sociability.

A Sham-Controlled Study of Neurofeedback for Pain Management.

BackgroundNeurofeedback (NFB) attempts to alter the brain’s electrophysiological activity and has shown potential as a pain management technique. Existing studies, however, often lack appropriate control groups or fail to assess whether electrophysiological activity has been successfully regulated. The current study is a randomized controlled trial comparing changes in brain activity and pain during NFB with those of a sham-control group.MethodsAn experimental pain paradigm in healthy participants was used to provide optimal control of pain sensation. Twenty four healthy participants were blind randomized to receive either 10 × NFB (with real EEG feedback) or 10 × sham (with false EEG feedback) sessions during noxious cold stimulation. Prior to actual NFB training, training protocols were individually determined for each participant based on a comparison of an initial 32-channel qEEG assessment administered at both baseline and during an experimental pain task. Each individual protocol was based on the electrode site and frequency band that showed the greatest change in amplitude during pain, with alpha or theta up-regulation at various electrode sites (especially Pz) the most common protocols chosen. During the NFB sessions themselves, pain was assessed at multiple times during each session on a 0–10 rating scale, and ANOVA was used to examine changes in pain ratings and EEG amplitude both across and during sessions for both NFB and sham groups.ResultsFor pain, ANOVA trend analysis found a significant general linear decrease in pain across the 10 sessions (p = 0.015). However, no significant main or interaction effects of group were observed suggesting decreases in pain occurred independently of NFB. For EEG, there was a significant During Session X Group interaction (p = 0.004), which indicated that EEG amplitude at the training site was significantly closer to the target amplitude for the NFB compared to the sham group during painful stimulation, but this was only the case at the beginning of the cold task.ConclusionWhile these results must be interpreted within the context of an experimental pain model, they underline the importance of including an appropriate comparison group to avoid attributing naturally occurring changes to therapeutic effects.

Passive transfer of fibromyalgia symptoms from patients to mice.

Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.

Noxious cold stimulation: pro–con perspectives on the hypothermic effect on experimentally evoked cough

We read with great interest in the recent article by Hilton et al. [1] published in the European Respiratory Journal , about the effect of pain conditioning on experimentally evoked cough; the hypothesis and protocol are well thought out. The study showed that noxious cold-water-induced pain significantly reduced capsaicin-evoked cough; however, it was less effective in refractory chronic cough (RCC) patients than healthy volunteers. The results indicated that endogenous inhibitory control mechanisms, especially those activated by noxious stimuli-inducing pain (conditioned pain modulation, CPM), can modulate cough response evoked by capsaicin. Impairment of such mechanisms may contribute to persistent coughing in RCC patients. The cold stimulation effect on the body may have bidirectional influences on cough response in differential exposure temperature and areas <https://bit.ly/38nVohD>

Linking Pain Sensation to the Autonomic Nervous System: The Role of the Anterior Cingulate and Periaqueductal Gray Resting-State Networks.

There are bi-directional interactions between the autonomic nervous system (ANS) and pain. This is likely underpinned by a substantial overlap between brain areas of the central autonomic network and areas involved in pain processing and modulation. To date, however, relatively little is known about the neuronal substrates of the ANS-pain association. Here, we acquired resting state fMRI scans in 21 healthy subjects at rest and during tonic noxious cold stimulation. As indicators of autonomic function, we examined how heart rate variability (HRV) frequency measures were influenced by tonic noxious stimulation and how these variables related to participants’ pain perception and to brain functional connectivity in regions known to play a role in both ANS regulation and pain perception, namely the right dorsal anterior cingulate cortex (dACC) and periaqueductal gray (PAG). Our findings support a role of the cardiac ANS in brain connectivity during pain, linking functional connections of the dACC and PAG with measurements of low frequency (LF)-HRV. In particular, we identified a three-way relationship between the ANS, cortical brain networks known to underpin pain processing, and participants’ subjectively reported pain experiences. LF-HRV both at rest and during pain correlated with functional connectivity between the seed regions and other cortical areas including the right dorsolateral prefrontal cortex (dlPFC), left anterior insula (AI), and the precuneus. Our findings link cardiovascular autonomic parameters to brain activity changes involved in the elaboration of nociceptive information, thus beginning to elucidate underlying brain mechanisms associated with the reciprocal relationship between autonomic and pain-related systems.

Autoantibodies produce pain in complex regional pain syndrome by sensitizing nociceptors.

Complex regional pain syndrome (CRPS) is a posttraumatic pain condition with an incompletely understood pathophysiological basis. Here, we have examined the cellular basis of pain in CRPS using behavioral and electrophysiological methods in mice treated with IgG from CRPS patients, in combination with a paw incision. Mice were subjected to a hind paw skin-muscle incision alone, or in combination with administration of IgG purified from either healthy control subjects or patients with persistent CRPS. Nociceptive function was examined behaviorally in vivo, and electrophysiologically in vitro using skin-nerve preparations to study the major classes of mechanosensitive single units. Administration of IgG from CRPS patients exacerbated and prolonged the postsurgical hypersensitivity to noxious mechanical, cold, and heat stimulation, but did not influence tactile sensitivity after a paw incision. Studies of IgG preparations pooled from patient cohorts (n = 26-27) show that pathological autoantibodies are present in the wider population of patients with persistent CRPS, and that patients with more severe pain have higher effective autoantibody titres than patients with moderate pain intensity. Electrophysiological investigation of skin-nerve preparations from mice treated with CRPS IgG from a single patient identified both a significantly increased evoked impulse activity in A and C nociceptors, and an increased spontaneous impulse rate in the intact saphenous nerve. Our results show that painful hypersensitivity in persistent CRPS is maintained by autoantibodies, which act by sensitizing A and C nociceptors.

The relationship between sensitivity to pain and conditioned pain modulation in healthy people

BackgroundThe relationship between sensitivity to pain and conditioned pain modulation (CPM) – a paradigm reflecting the activity of the endogenous descending analgesic system - is still unclear. This study aimed at investigating CPM magnitude in two distinct subgroups of healthy subjects, presenting low vs. high sensitivity to pain (LSP vs. HSP, respectively), by employing two different thermal paradigms of CPM. MethodNinety-five healthy subjects (out of 293 tested) were identified as LSP (n = 48) or HSP (n = 47) according to their tolerance time to noxious cold stimulation (Cold Pressor Test, 1 °C). All subjects were exposed to two different paradigms of CPM: 1) Fixed temperature ‘test-pain’ (TP) where phasic, fixed painful heat stimuli of 47 °C were administered before and during a prolonged ‘conditioning stimulus’ (cold water at 12 °C for 30 s); and 2) Individually based 'pain-60' where TP was determined as the temperature that induced pain at a magnitude of 60 on a 0–100 rating scale (with the same conditioning stimulus). ResultUsing both thermal paradigms, LSP subjects showed decreased CPM magnitudes in comparison to HSP (p < 0.0001 in both paradigms). Within each group, no differences in the magnitudes of CPM were found between the two paradigms. ConclusionThese findings show that regardless of the thermal CPM paradigm employed, healthy individuals exhibiting low sensitivity to pain have a low pain inhibition profile and vice-versa. It is suggested that in healthy subjects, pain sensitivity predisposes the magnitude of CPM and not the other way around.

TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold

Sensory neurons innervating the dental pulp have unique morphological and functional characteristics compared to neurons innervating other tissues. Stimulation of dental pulp afferents whatever the modality or intensity of the stimulus, even light mechanical stimulation that would not activate nociceptors in other tissues, produces an intense pain. These specific sensory characteristics could involve receptors of the Transient Receptor Potential channels (TRP) family. In this study, we compared the expression of the cold sensitive receptors TRPM8 and TRPA1 in trigeminal ganglion neurons innervating the dental pulp, the skin of the cheek or the buccal mucosa and we evaluated the involvement of these receptors in dental pulp sensitivity to cold. We showed a similar expression of TRPM8, TRPA1 and CGRP in sensory neurons innervating the dental pulp, the skin or the mucosa. Moreover, we demonstrated that noxious cold stimulation of the tooth induced an overexpression of cFos in the trigeminal nucleus that was not prevented by the genetic deletion of TRPM8 or the administration of the TRPA1 antagonist HC030031. These data suggest that the unique sensory characteristics of the dental pulp are independent to TRPM8 and TRPA1 receptors expression and functionality.

Machine-learned analysis of quantitative sensory testing responses to noxious cold stimulation in healthy subjects.

Pain in response to noxious cold has a complex molecular background probably involving several types of sensors. A recent observation has been the multimodal distribution of human cold pain thresholds. This study aimed at analysing reproducibility and stability of this observation and further exploration of data patterns supporting a complex background. Pain thresholds to noxious cold stimuli (range 32-0°C, tonic: temperature decrease -1°C/s, phasic: temperature decrease -8°C/s) were acquired in 148 healthy volunteers. The probability density distribution was analysed using machine-learning derived methods implemented as Gaussian mixture modeling (GMM), emergent self-organizing maps and self-organizing swarms of data agents. The probability density function of pain responses was trimodal (mean thresholds at 25.9, 18.4 and 8.0°C for tonic and 24.5, 18.1 and 7.5°C for phasic stimuli). Subjects' association with Gaussian modes was consistent between both types of stimuli (weighted Cohen's κ=0.91). Patterns emerging in self-organizing neuronal maps and swarms could be associated with different trends towards decreasing cold pain sensitivity in different Gaussian modes. On self-organizing maps, the third Gaussian mode emerged as particularly distinct. Thresholds at, roughly, 25 and 18°C agree with known working temperatures of TRPM8 and TRPA1 ion channels, respectively, and hint at relative local dominance of either channel in respective subjects. Data patterns suggest involvement of further distinct mechanisms in cold pain perception at lower temperatures. Findings support data science approaches to identify biologically plausible hints at complex molecular mechanisms underlying human pain phenotypes. Sensitivity to pain is heterogeneous. Data-driven computational research approaches allow the identification of subgroups of subjects with a distinct pattern of sensitivity to cold stimuli. The subgroups are reproducible with different types of noxious cold stimuli. Subgroups show pattern that hints at distinct and inter-individually different types of the underlying molecular background.

Activation of Transient Receptor Potential Melastatin Subtype 8 Attenuates Cold-Induced Hypertension Through Ameliorating Vascular Mitochondrial Dysfunction.

BackgroundEnvironmental cold‐induced hypertension is common, but how to treat cold‐induced hypertension remains an obstacle. Transient receptor potential melastatin subtype 8 (TRPM8) is a mild cold‐sensing nonselective cation channel that is activated by menthol. Little is known about the effect of TRPM8 activation by menthol on mitochondrial Ca2+ homeostasis and the vascular function in cold‐induced hypertension.Methods and ResultsPrimary vascular smooth muscle cells from wild‐type or Trpm8−/− mice were cultured. In vitro, we confirmed that sarcoplasmic reticulum–resident TRPM8 participated in the regulation of cellular and mitochondrial Ca2+ homeostasis in the vascular smooth muscle cells. TRPM8 activation by menthol antagonized angiotensin II induced mitochondrial respiratory dysfunction and excess reactive oxygen species generation by preserving pyruvate dehydrogenase activity, which hindered reactive oxygen species–triggered Ca2+ influx and the activation of RhoA/Rho kinase pathway. In vivo, long‐term noxious cold stimulation dramatically increased vasoconstriction and blood pressure. The activation of TRPM8 by dietary menthol inhibited vascular reactive oxygen species generation, vasoconstriction, and lowered blood pressure through attenuating excessive mitochondrial reactive oxygen species mediated the activation of RhoA/Rho kinase in a TRPM8‐dependent manner. These effects of menthol were further validated in angiotensin II–induced hypertensive mice.ConclusionsLong‐term dietary menthol treatment targeting and preserving mitochondrial function may represent a nonpharmaceutical measure for environmental noxious cold–induced hypertension.

Activity and connectivity changes of central projection areas revealed by functional magnetic resonance imaging in NaV1.8-deficient mice upon cold signaling

The voltage-gated sodium channel subtype NaV1.8 is expressed in the peripheral nervous system in primary afferent nociceptive C-fibers and is essential for noxious cold signaling. We utilized functional magnetic resonance imaging on NaV1.8-deficient (NaV1.8−/−) compared with wildtype (WT) mice to identify brain structures decoding noxious cold and/or heat signals. In NaV1.8−/− mice functional activity patterns, activated volumes and BOLD signal amplitudes are significantly reduced upon noxious cold stimulation whereas differences of noxious heat processing are less pronounced. Graph-theoretical analysis of the functional connectivity also shows dramatic alterations in noxious cold sensation in NaV1.8−/− mice and clearly reduced interactions between certain brain structures. In contrast, upon heat stimulation qualitatively quite the same functional connectivity pattern and consequently less prominent connectivity differences were observed between NaV1.8−/− and WT mice. Thus, the fact that NaV1.8−/− mice do not perceive nociceptive aspects of strong cooling in contrast to their WT littermates seems not only to be a pure peripheral phenomenon with diminished peripheral transmission, but also consists of upstream effects leading to altered subsequent nociceptive processing in the central nervous system and consequently altered connectivity between pain-relevant brain structures.

Analysis of C-reactive protein (CRP) levels in pain patients – Can biomarker studies lead to better understanding of the pathophysiology of pain?

In this issue of the Scandinavian Journal of Pain, Michele Sterling and co-authors present data showing that blood levels of the inflammatory biomarker serum C-reactive protein (CRP) seem to correlate to fMRI responses in regional brain areas, activated by noxious cold stimulation of the hand in patients with chronic whiplash associated disorders (WAD) [1]. The activated brain regions included the anterior insula, posterior parietal cortex, caudate and thalamus. The levels of TNF-alpha were not related to cerebral fMRI changes during pain stimuli, but a moderate positive correlation was found between blood levels of TNF and the psychological variable of pain catastrophizing. The study shows the interesting possibility to use analysis of biomarkers in blood as a way for deeper understanding of the biological aspect of pain, this elusive “bio-psycho-social” construct, combined with “imaging biomarkers” using fMRI. I think it is realistic to say that in the parts of the medical community, pain patients and pain treatment often are considered as “low status” work, and difficult to handle. One reason behind this view may be the fact that the golden standard of pain assessment is based upon the patient’s self-report only, and that objective, measurable findings usually are absent. Of course, we must trust the patient’s report, but I often wish that we had better tools to understand the nature of pain and its pathophysiology. “We need a CRP for pain”, a colleague pain clinician once said, “some lab test that would show that there is something measurable going on in the pain patient. This would improve the respect for the pain patients from the caregivers, and give the field of pain medicine a better status” (personal communication, Jens Draiby, 2014).

Serum C-reactive protein levels predict regional brain responses to noxious cold stimulation of the hand in chronic whiplash associated disorders

Background and aimsWhiplash Associated Disorders (WAD) are a costly health burden. The condition is characterised by sensory disturbances such as widespread hyperalgesia likely indicative of central hyperexcitability. Recently elevated levels of pro-inflammatory biomarkers have also found in acute and chronic WAD. The aim of this cross-sectional study was to investigate the relationship between inflammatory biomarkers and pain processing in people with persistent whiplash associated disorders (WAD). MethodsTwenty one participants with chronic whiplash (>3 months) were recruited. Venous blood samples were collected and assays performed for C-reactive protein (CRP) and TNF-α. Blood oxygen level-dependent (BOLD) contrast images of the brain were acquired with a Siemens 1.5T MRI scanner during repeated 24s stimulus blocks of innocuous or painful stimuli (thumbnail pressure and cold stimulation of dorsum of hand) separated by 36s inter-stimulus intervals. Stimulus intensities used during scanning were at the level of participants’ thresholds for moderate pain. Parameter estimates representing BOLD signal increases during painful events from each participant were tested for associations with inflammatory biomarkers. ResultsClinically relevant levels of CRP and TNF-α were found in 33% and 38% of participants. Levels of CRP showed a positive correlation with levels of cold pain activation in brain regions including the anterior insula, posterior parietal cortex, caudate and thalamus (pcorrected<0.05). Levels of TNF-α were not related to activation levels during either noxious pressure or cold. Pressure pain activations also did not show a relationship with CRP levels. ConclusionsShared variance between inflammation and increased levels of regional pain-related activation in people with persistent whiplash symptoms is apparent for cold, but not pressure stimuli. ImplicationsThe results highlight cold pain processing as an important aspect of whiplash chronicity, although the implications of this modality-specific effect are not readily apparent.

Age‐related changes in peripheral nociceptor function (659.2)

Effective and safe pain management in the elderly is a major medical challenge. Furthermore, little is known regarding the effect of aging on nociceptor (pain‐sensing neuron) responsiveness or the function of opioid receptors expressed on nociceptors. Here, we compared the effects of the sensitizing agent, bradykinin (BK), and delta and kappa opioid receptor (DOR, KOR) agonists on nociceptors in young (4‐months‐old) and aged (26‐months‐old) Fisher x Brown Norway rats. Behavioral responses to noxious heat, cold, or mechanical stimulation were determined following intraplantar injections of BK. For all three stimuli, aged rats had a greater allodynic response to BK. In primary cultures, activation of phospholipase C in nociceptors from aged rats was more sensitive to BK than those from young rats. In addition, both opioid agonists, SNC80 (DOR) and Salvinorin A (KOR), produced greater antinociceptive effects in aged rats compared to young rats. Similarly, opioid receptor‐mediated inhibition of adenylyl cyclase activity was greater in nociceptors from aged rats. Overall, our results indicate that aging enhances allodynic effects of the inflammatory mediator, BK, as well as increases antinociceptive effects of opioid agonists. We propose that peripherally‐restricted opioids may be a valuable analgesic strategy for treating pain in the elderly.Grant Funding Source: Supported by T32DA031115, Baptist Health Foundation, Nathan Shock Center of Excellence AG013319

Hypoxia-Inducible Factor 1 Regulates Heat and Cold Pain Sensitivity and Persistence

The present study assessed the functions of the transcription factor hypoxia-inducible factor (HIF) in sensory neurons in models of acute, inflammatory, ischemic, and neuropathic pain. The alpha subunit, HIF1α, was specifically deleted in neurons of the dorsal root ganglia by mating HIF1α(fl/fl) mice with SNScre mice. SNS-HIF1α(-/-) mice were more sensitive to noxious heat and cold pain stimulation than were HIF1α(fl/fl) control mice. They also showed heightened first-phase nociceptive responses in the formalin and capsaicin tests with increased numbers of cFos-positive neurons in the dorsal horn, and intensified hyperalgesia in early phases after paw inflammation and hind limb ischemia/reperfusion. The behavioral cold and heat pain hypersensitivity was explained by increased calcium fluxes after transient receptor potential channel activation in primary sensory neurons of SNS-HIF1α(-/-) mice and lowered electrical activation thresholds of sensory fibers. SNS-HIF1α(-/-) mice however, developed less neuropathic pain after sciatic nerve injury, which was associated with an abrogation of HIF1-mediated gene up-regulation. The results suggest that HIF1α is protective in terms of acute heat and cold pain but in case of ongoing activation in injured neurons, it may promote the development of neuropathic pain. The duality of HIF1 in pain regulation may have an impact on the side effects of drugs targeting HIF1, which are being developed, for example, as anticancer agents. Specifically, in patients with cancer neuropathy, however, temporary HIF1 inhibition might provide a welcome combination of growth and pain reduction.

Changes in the modulation of spinal pain processing are related to severity in irritable bowel syndrome

In irritable bowel syndrome (IBS) patients can be divided in two groups according to inhibition or facilitation of the RIII nociceptive spinal reflex induced by rectal distension. We further investigated the differences in pain processes in these two groups and their relationship to clinical symptoms. This study included 10 female IBS-C patients with facilitation (Group F) and 10 patients with inhibition (Group I) of the RIII reflex recorded on the left lower limb during slow-ramp rectal distension, and 11 healthy female volunteers. Diffuse noxious inhibitory control (DNIC)-induced inhibition was assessed by measuring the effects of noxious cold stimulation of the right hand on the RIII reflex and the concomitant sensation of pain. Functional magnetic resonance imaging (fMRI) was performed to compare the changes in brain activity induced by painful and non painful rectal distension. Irritable bowel syndrome symptom severity, mood, anxiety, and catastrophizing were also systematically assessed. Unlike the patients of Group I and healthy volunteers, Group F patients displayed no inhibition of the RIII reflex or of concomitant pain sensation during immersion of the hand in ice-cold water. The reduction of the inhibition induced by heterotopic noxious stimuli was directly correlated with the severity of IBS symptoms, but not with psychological symptoms. The fMRI study showed that non-painful and painful rectal distension induced similar changes in brain activity in the two groups of patients. Alterations of the modulation of spinal pain processing in IBS correlates with symptom severity but not with psychological factors or brain activity.

Evaluation of antinociceptive and antioxidant properties of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one in mice

The aim of this study was to evaluate the influence of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one (LPP1) on nociceptive thresholds in mouse models of persistent pain. Influence of LPP1 on motor coordination and its antioxidant capacity in mouse brain tissue homogenates were also assessed. Pain sensitivity thresholds in animals treated with LPP1 were established using 5 % formalin solution in normoglycemic mice and in streptozotocin (STZ)-treated diabetic mice in the von Frey, hot plate, innocuous, and noxious cold water tests (water at 10 °C and 4 °C, respectively). Motor deficits were assessed in the rotarod test, whereas antioxidant capacities were evaluated using ferric reducing ability of plasma (FRAP) assay, catalase (CAT), and superoxide dismutase (SOD) activities. LPP1was antinociceptive in both phases of the formalin test, in particular, in the late phase (at doses 0.9–30 mg/kg for 66–99 % vs. control normoglycemic mice) and in a statistically significant manner increased nociceptive thresholds in response to mechanical, heat, and noxious cold stimulation in neuropathic mice (at 30 mg/kg for 274, 192, and 316 %, respectively vs. diabetic control). LPP1 did not impair motor coordination of mice in the rotarod revolving at 6 or 18 rpm. In brain tissue homogenates, it demonstrated antioxidant capacity in FRAP assay and increased SOD activity for 63 % (acute administration) and 28 % (chronic administration) vs. control. No influence on CAT activity was observed. LPP1 has significant antinociceptive properties in the formalin model and elevates pain thresholds in neuropathic mice. It has antioxidant capacity and is devoid of negative influence on animals' motor coordination.

Mechanisms of individual differences in heterotopic noxious analgesia (DNIC), an fMRI study

Pain responses can be suppressed by heterotopic continuous noxious conditioning, e.g. continuous noxious cold stimulation.

The impact of prenatal stress on basal nociception and evoked responses to tail-docking and inflammatory challenge in juvenile pigs

The consequences of tail-docking (at 2–4days) and prenatal stress (maternal social stress during the 2nd third of pregnancy) on baseline nociceptive thresholds and responses to acute inflammatory challenge were investigated in juvenile pigs in two studies. Nociceptive thresholds were assessed on the tail root and on the hind foot using noxious mechanical and cold stimulation before and after acute inflammatory challenge by intradermal injection of 30μg capsaicin (study 1) or 3% carrageenan (study 2) into the tail root. Four groups of 8 (study 1, n=14–16 pigs/treatment) or 5 (study 2, n=6 pigs/treatment/sex) week-old pigs were exposed to the main factors: maternal stress and treatment (docked vs. intact tails). In study 1, tail docking did not significantly alter thresholds to noxious mechanical stimulation, whilst prenatally stressed pigs had significantly higher baseline thresholds to noxious mechanical stimulation on the tail root and on the hind foot than unstressed pigs, whether tail-docked or intact. Capsaicin injection induced localised mechanical allodynia around the tail root in all treatment groups, but had no effect on noxious plantar mechanical responses; however prenatally stressed offspring exhibited significantly attenuated response thresholds to capsaicin compared to controls. In study 2 tail docking did not alter thresholds to either mechanical or noxious cold stimulation. Baseline response durations to noxious cold stimulation of the tail root were significantly shorter in both sexes of prenatally stressed pigs, whilst male but not female prenatally stressed pigs exhibited significantly higher baseline thresholds to mechanical stimulation than controls, although results in female pigs tended towards significance. Carrageenan injection into the tail root induced localised mechanical and cold allodynia in all treatment groups, effects that were attenuated in prenatally stressed pigs. Collectively, these findings indicate that prenatal stress can induce long-term alterations in nociceptive responses, manifest as a reduced sensitivity to noxious mechanical and cold stimulation and evoked inflammatory allodynia. Neonatal tail-docking does not lead to long-term alterations in nociception in pigs.

Dorsal root ganglion neurons respond with prolonged extracellular signal-regulated protein kinase phosphorylation following noxious heat and cold stimulation

In the present study the time course of extracellular signal-regulated protein kinase phosphorylation (pERK1/2 appearance) in lumbar sensory dorsal root ganglia (DRG) was determined following a 5-min noxious heat or a noxious cold stimulus to the hind paw of the rat. The thermal stimuli were chosen to activate transient receptor potential (TRP) channels, but not to induce tissue damage. A quantitative analysis of phospho-ERK1/2 was performed by protein extraction and Western blot analysis. Western blot analysis showed that following the heat stimulus, phosphorylation of ERK1/2 increased 2-3-fold between 10 and 30min in the DRG on the ipsilateral side. High levels were maintained from 30min up to 16h. Following the cold stimulus to the paw, pERK1/2 immediately increased 2-fold within 2min in the DRG on the ipsilateral side, it declined within 2h and reached a second peak at 4h. In the DRGs on the contralateral side of the paw's heat or cold immersion the pERK1/2 remained low at all time points investigated. Fluorescence immunohistochemistry of the DRG following the thermal stimuli revealed an increased cytoplasmic staining for pERK1/2 in neurons. The present results show that following a 5-min nociceptive thermal stimulus sensory neurons respond with a characteristic long-lasting phosphorylation of ERK1/2.