Noxious Heat Stimuli Research Articles

Defensive Behavior against Noxious Heat Stimuli Is Declined with Aging Due to Decreased Pain-Associated Gene Expression in Drosophila

Aging is defined as a collective process that alters organism’s functional capacity and appearance over the course of life. Apart from an increase in susceptibility to many diseases, aging affects the cellular system that is responsible for decoding painful stimuli. Yet, aging-associated molecular mechanisms of pain perception remains elusive. Using Drosophila, we showed a decrease in temperature tolerance and a reduction in high temperature thermal avoidance with aging. Locomotor activity assay demonstrated that the age-dependent changes in heat nociception did not stem from the general decline in muscular activity. However, we identified pain-related gene expression alteration with aging. We anticipate that our findings would help opening a new window onto developing the optimal pain treatment for the elderly.

Activated platelets release sphingosine 1-phosphate and induce hypersensitivity to noxious heat stimuli in vivo.

At the site of injury activated platelets release various mediators, one of which is sphingosine 1-phosphate (S1P). It was the aim of this study to explore whether activated human platelets had a pronociceptive effect in an in vivo mouse model and whether this effect was based on the release of S1P and subsequent activation of neuronal S1P receptors 1 or 3. Human platelets were prepared in different concentrations (105/μl, 106/μl, 107/μl) and assessed in mice with different genetic backgrounds (WT, S1P1fl/fl, SNS-S1P1−/−, S1P3−/−). Intracutaneous injections of activated human platelets induced a significant, dose-dependent hypersensitivity to noxious thermal stimulation. The degree of heat hypersensitivity correlated with the platelet concentration as well as the platelet S1P content and the amount of S1P released upon platelet activation as measured with LC MS/MS. Despite the significant correlations between S1P and platelet count, no difference in paw withdrawal latency (PWL) was observed in mice with a global null mutation of the S1P3 receptor or a conditional deletion of the S1P1 receptor in nociceptive primary afferents. Furthermore, neutralization of S1P with a selective anti-S1P antibody did not abolish platelet induced heat hypersensitivity. Our results suggest that activated platelets release S1P and induce heat hypersensitivity in vivo. However, the platelet induced heat hypersensitivity was caused by mediators other than S1P.

Effectiveness of High-Frequency Electrical Stimulation Following Sensitization With Capsaicin

Although nonnoxious, high-frequency electrical stimulation applied segmentally (ie, conventional transcutaneous electrical nerve stimulation [TENS]) has been proposed to modulate pain, the mechanisms underlying analgesia remain poorly understood. To further elucidate how TENS modulates pain, we examined evoked responses to noxious thermal stimuli after the induction of sensitization using capsaicin in healthy volunteers. We hypothesized that sensitization caused by capsaicin application would unmask TENS analgesia, which could not be detected in the absence of sensitization. Forty-nine healthy subjects took part in a series of experiments. The experiments comprised the application of topical capsaicin (.075%) on the left hand in the C6 dermatome, varying the location of TENS (segmental, left C6 dermatome, vs extrasegmental, right shoulder), and assessing rating of perception (numeric rating scale: 0–10) and evoked potentials to noxious contact heat stimuli. The extrasegmental site was included as a control condition because previous studies indicate no analgesic effect to remote conventional TENS. Conventional TENS had no significant effect on rating or sensory evoked potentials in subjects untreated with capsaicin. However, segmental TENS applied in conjunction with capsaicin significantly reduced sensation to noxious thermal stimuli following a 60-minute period of sensitization. PerspectiveThe study indicates that sensitization with capsaicin unmasks the analgesic effect of conventional TENS on perception of noxious contact heat stimuli. Our findings indicate that TENS may be interacting segmentally to modulate distinct aspects of sensitization, which in turn results in analgesia to thermal stimulation.

Anatomical evidence that the uninjured adjacent L4 nerve plays a significant role in the development of peripheral neuropathic pain after L5 spinal nerve ligation in rats.

Rats develop hyperalgesia and allodynia in the hind paw after L5 spinal nerve ligation. Phosphorylated extracellular regulated kinase (pERK) was used as a pain marker to investigate the potential role of adjacent uninjured L4 nerve in the development of heat hyperalgesia after L5 nerve injury. Left L5 nerve was ligated and sectioned in rats. Three days later, rats were randomly assigned to five groups; each had both hind paws immersed in water at different temperatures (no heat, 37, 42, 47, and 52 °C) under sevoflurane anesthesia for 2 minutes. Five minutes after stimulation the rats were sacrificed and sections of L3-L6 spinal segments were stained immunocytochemically with pERK antibody. pERK immunoreactivity, which is not detectable in the normal spinal cord, was discernible in neurons (not glia) of the superficial dorsal horn after noxious heat stimuli. pERK-positive neurons clearly overlapped in laminae I-II with normal unmyelinated and thin myelinated afferents labeled with calcitonin gene-related peptide and isolectin B4, and injured unmyelinated afferents labeled with vasoactive intestinal polypeptide. There was a linear increase in pERK immunoreactivity on both sides with an increase in temperature. Importantly, the number of positive pERK neurons was significantly higher in the ipsilateral side of L4 spinal segment, which receives innervation from uninjured L4 nerve, compared with the contralateral control side, which receives both uninjured L4 and L5 spinal nerves. The data demonstrate that the uninjured L4 nerve plays an important role in the development of heat hyperalgesia at the spinal cord level after L5 nerve injury.

Temporal and spatial aspects of experimental tonic pain: Understanding pain adaptation and intensification.

The underlying mechanisms of adaptations to pain are unclear. In order to explore whether central or peripheral mechanisms predominate, the effects of two centrally mediated phenomena - spatial summation of pain (SSP) and transcutaneous electrical nerve stimulation (TENS) - were examined. The effect of the degree of painfulness, rather than absolute stimulation intensity, was also examined. Seventeen participants received several series of individually adjusted tonic noxious-heat stimuli (300 s), inducing an initial perceived pain of 2 (mild pain), 4 (moderate pain) and 6 (strong pain) on a visual analogue scale (VAS). The stimuli were administered to small (2.25 cm2) and large (9 cm2) areas to produce SSP and also during TENS treatment, during which 12 VAS ratings were obtained. Adaptation occurred during VAS-2 stimulation and was minimal, followed by intensification during VAS-4 stimulation, whereas VAS-6 stimulation always induced pain intensification. TENS failed to produce analgesia and SSP did not affect adaptation but affected intensification. Stimulation temperatures affected the magnitude of adaptation and intensification within each degree of painfulness. The mathematical models that best fitted the time trend with VAS-2 and VAS-4 were linear, whereas a power function best fitted VAS-6 stimulation. The mathematical models and the lack of effect of SSP on adaptation suggest that its dominant component is peripheral. Whereas relative painfulness determines whether pain adaptation or intensification occurs (probably a defence mechanism), absolute stimulation intensities influence the magnitude of the effect. Pain intensification is differentially affected by probe size, depending upon the occurrence of initial adaptation.

3-iodothyroacetic acid, a metabolite of thyroid hormone, induces itch and reduces threshold to noxious and to painful heat stimuli in mice.

Itch is associated with increased sensitization to nociceptive stimuli. We investigated whether 3-iodothyroacetic acid (TA1), by releasing histamine, induces itch and increases sensitization to noxious and painful heat stimuli. Itch was evaluated after s.c. administration of TA1 (0.4, 1.32 and 4 μg·kg(-1) ). Mice threshold to noxious (NHT) and to painful heat stimuli were evaluated by the increasing-temperature hot plate (from 45.5 to 49.5°C) or by the hot plate (51.5°C) test, respectively, 15 min after i.p. injection of TA1 (0.4, 1.32 and 4 μg·kg(-1) ). Itch, NHT and pain threshold evaluation were repeated in mice pretreated with pyrilamine. Itch and NHT were also measured in HDC(+/+) and HDC(-/-) following injection of saline or TA1 (1.32, 4 and 11 μg·kg(-1) ; s.c. and i.p.). pERK1/2 levels were determined by Western blot in dorsal root ganglia (DRG) isolated from CD1 mice 15 min after they received (i.p.): saline, saline and noxious heat stimulus (46.5°C), TA1 (0.1, 0.4, 1.32, 4 μg·kg(-1) ) or TA1 1.32 μg·kg(-1) and noxious heat stimulus. TA1 0.4 and 1.32 μg·kg(-1) induced itch and reduced NHT; pyrilamine pretreatment prevented both of these effects. TA1 4 μg·kg(-1) (i.p.) reduced pain threshold without inducing itch or modifying NHT. In HDC(-/-) mice, TA1 failed to induce itch and to reduce NHT. In DRG, pERK1/2 levels were significantly increased by noxious heat stimuli and by TA1 0.1, 0.4 and 1.32 μg·kg(-1) ; i.p. Increased TA1 levels induce itch and an enhanced sensitivity to noxious heat stimuli suggesting that TA1 might represent a potential cause of itch in thyroid diseases.

Failure of intrathecal ketorolac to reduce remifentanil-induced postinfusion hyperalgesia in humans

In rodents, acute exposure to opioids results in transient antinociception followed by longer lasting hypersensitivity to tactile or thermal stimuli, a phenomenon termed opioid-induced hyperalgesia. This hypersensitivity can be blocked or reversed by intrathecally administered cyclooxygenase inhibitors, including ketorolac, suggesting a role for spinal prostaglandins. In surgical patients, the dose of intraoperative opioid, particularly the short-acting drug, remifentanil, is directly related to increased pain and opioid requirements for many hours postoperatively. In addition, experimentally induced tactile hypersensitivity in humans is exaggerated after cessation of remifentanil infusions. The degree of this experimental opioid-induced hyperalgesia is reduced by systemic treatment with cyclooxygenase inhibitors, and investigators have speculated that this reduction reflects the actions in the central nervous system, most likely in the spinal cord. To test this hypothesis, we measured cerebrospinal fluid prostaglandin E2 concentrations during and after remifentanil infusion in 30 volunteers. These volunteers received intrathecal ketorolac or saline in a random, blinded manner during intravenous remifentanil infusion after generation of hypersensitivity by topical capsaicin. Remifentanil reduced pain to noxious heat stimuli and reduced areas of capsaicin-induced hypersensitivity similarly in those receiving intrathecal ketorolac or saline. The primary outcome measure, area of capsaicin-induced hypersensitivity after stopping remifentanil, showed a similar increase in those receiving ketorolac as in those receiving saline. Cerebrospinal fluid prostaglandin E2 concentrations did not increase during postinfusion hyperalgesia compared with those during infusion, and they were not increased during infusion compared with those in historical controls. These data fail to support the hypothesis that acute opioid-induced hyperalgesia reflects spinal cyclooxygenase activation causing central sensitization.

Time course of hyperalgesia in the rat chronic constriction injury model of neuropathic pain

Background: Patients with insults to the somatosensory system may suffer from great debilitating pain with the presence of sharp and burning neuropathic pain that is largely resistant to treatment. This pain is spontaneous in most patients but may manifest as both hyperalgesia and/or allodynia. Objective: The aim of the current research was to investigate changes in the latency of paw withdrawal to noxious heat stimuli after nerve injury. Material and methods: The experiments were performed in six male Lewis rats (Charles River Laboratories, Wilmington, MA, USA). Chronic Constriction Injury (CCI) was performed on three rats and the other three rats were subjected to sham operation. The rats underwent three rounds of habituation and baseline measurements of latencies of ipsilateral paw withdrawal were taken one day before the operation (Day 1). After the operation, heat latencies of ipsilateral paw withdrawal were measured in CCI and sham rats on Days 1, 3, 6, 8, 10, 13, 15 and 21. Result: The results show that sham rats did not develop hyperalgesia but in CCI rats there was a significant decrease in the heat latencies between baseline and Day 8. Over the rest of the time points, the mean latency started to increase indicting recovery. There was some variability in both groups. Conclusions: These changes in the time course of hyperalgesia may be related to immune cell activation and cytokine production at different time points. This was an animal study, yet it may pave the way to understanding similar conditions in humans. Acknowledgements: Dr Karima Kahlat for supervising this project.

MRI scanner environment increases pain perception in a standardized nociceptive paradigm.

Functional magnetic resonance imaging (MRI) has been widely used in neuroscientific studies to investigate neural correlates of perception and higher cognitive functions. Early on, the MR-scanning procedure itself has been identified to create discomfort and anxiety in some individuals, which may influence task performance and perception. The present study analyzed behavioral differences in pain intensity ratings obtained in two distinct situations: MR environment and laboratory setting. Within our longitudinal study design twenty healthy volunteers were exposed daily to an identical paradigm consisting of 60 repeated noxious heat stimuli (46°C) on 21 consecutive days. After each block of ten stimuli, participants were prompted to rate pain intensity on a visual analog scale (VAS). On days 1, 8, 14, and 21 ratings scores were obtained during a functional imaging scan, whereas on the remaining days the sessions were conducted in a laboratory. It has come to our attention that pain intensity ratings acquired in MR environment were significantly higher than behavioral data collected in the lab setting. Given that the stimuli were standardized and no task or distraction confounded the ratings, it is likely that the attentional focus on noxious stimulation was identical in both conditions. It seems that the highly artificial scanner environment as such is sufficient to increase awareness/alertness. Given that salience rather than pure nociceptive input has been suggested to explain functional imaging results in painful conditions, these findings highlight concerns regarding the comparability of behavioral data assembled across inconsistent settings.

Modality and sex differences in pain sensitivity during human endotoxemia.

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's.

The Role of PPK26 in Drosophila Larval Mechanical Nociception

In Drosophila larvae, the class IV dendritic arborization (da) neurons are polymodal nociceptors. Here, we show that ppk26 (CG8546) plays an important role in mechanical nociception in class IV da neurons. Our immunohistochemical and functional results demonstrate that ppk26 is specifically expressed in class IV da neurons. Larvae with mutant ppk26 showed severe behavioral defects in a mechanical nociception behavioral test but responded to noxious heat stimuli comparably to wild-type larvae. In addition, functional studies suggest that ppk26 and ppk (also called ppk1) function in the same pathway, whereas piezo functions in a parallel pathway. Consistent with these functional results, we found that PPK and PPK26 are interdependent on each other for their cell surface localization. Our work indicates that PPK26 and PPK might form heteromeric DEG/ENaC channels that are essential for mechanotransduction in class IV da neurons.

Chronic administration of amitriptyline differentially alters neuropathic pain-related behaviour in the presence and absence of a depressive-like phenotype

Chronic pain and depression share a complex, reciprocal relationship. Furthermore, in addition to treating depression, antidepressants such as amitriptyline are a first-line treatment for chronic pain conditions, indicating possible common neural substrates underlying both depression and pain. However, there is a paucity of studies examining the effect of antidepressant treatment on nociceptive and neuropathic pain responding in the presence of a depressive phenotype. The current study aimed to examine the effect of chronic amitriptyline administration on neuropathic pain-related behaviour and associated neuroinflammatory processes in the olfactory bulbectomised (OB) rat model of depression. Nociceptive responding to mechanical, innocuous cold or noxious heat stimuli in sham or OB rats was not altered by chronic amitriptyline administration. The induction of neuropathic pain following L5–L6 spinal nerve ligation (SNL) resulted in robust mechanical and cold allodynia and heat hyperalgesia in both sham and OB vehicle-treated animals. Chronic amitriptyline administration attenuated SNL-induced mechanical allodynia in both sham and OB rats at day 7 post-SNL, an effect which was enhanced and prolonged in OB rats. In comparison, chronic amitriptyline administration attenuated SNL-induced cold allodynia and heat hyperalgesia in sham, but not OB, rats. Evaluating the affective/motivational aspect of pain using the place escape avoidance paradigm revealed that OB-SNL rats exhibit reduced noxious avoidance behaviour when compared with sham counterparts, an effect not altered by chronic amitriptyline administration. Chronic amitriptyline administration prevented the increased expression of GFAP, IL-10 and CCL5, and enhanced the expression of TNFα, in the prefrontal cortex of OB-SNL rats. In conclusion, these data demonstrate that chronic amitriptyline differentially alters somatic nociceptive responding following peripheral nerve-injury, depending on stimulus modality and the presence or absence of a depressive-like phenotype, an effect which may involve modulation of neuroinflammatory processes.

Well-loved music robustly relieves pain: a randomized, controlled trial.

Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly preferred music. A two-session experiment was performed with 48 healthy, pain experiment-naïve participants. In a first cohort, 36 were randomized into 3 treatment groups, including music enhanced with positive expectancy, non-musical sound enhanced with positive expectancy, and no expectancy enhancement. A separate replication cohort of 12 participants received only expectancy-enhanced music following the main experiment to verify the results of expectancy-manipulation on music. Primary outcome measures included the change in subjective pain ratings to calibrated experimental noxious heat stimuli, as well as changes in treatment expectations. Without conditioning, expectations were strongly in favor of music compared to non-musical sound. While measured expectations were enhanced by conditioning, this failed to affect either music or sound analgesia significantly. Strongly preferred music on its own was as pain relieving as conditioning-enhanced strongly preferred music, and more analgesic than enhanced sound. Our results demonstrate the pain-relieving power of personal music even over enhanced expectations.Trial InformationClinicaltrials.gov NCT01835275.

Effect of thermal stimulation on corticomotor excitability in patients with stroke.

This study examined the immediate effects of noxious and innocuous thermal stimulation intervention on corticomotor excitability for the paretic arm in patients with stroke. Sixteen patients with stroke for more than 3 mos were randomly assigned into the experimental and control groups. All participants received the thermal stimulation protocol on the affected arm for 30 mins. The experimental group received noxious heat (46°C-47°C) and cold (7°C-8°C) stimuli, and the control group received innocuous heat (40°C-41°C) and cold (20°C-21°C) stimuli. Corticomotor excitability was assessed to measure the motor threshold, size of cortical motor output map, and mean motor evoked potentials for the abductor pollicis brevis by focal transcranial magnetic stimulation before and after 30 mins of thermal stimulation intervention program. The findings of transcranial magnetic stimulation revealed a significant increase in map size of the affected hemisphere and mean motor evoked potentials in the experimental group. Moreover, significant differences in the change values of map size (7.0 [7.9] for the experimental group vs. -1.7 [2.9] for the control group, P = 0.03) and mean (SD) motor evoked potentials (0.4 [8.9] mV for the experimental group vs. -0.1 [0.1] mV for the control group, P = 0.03) were found. The preliminary results suggest that the noxious 30 mins of thermal stimulation intervention induced neurophysiologic changes in the motor cortex of the lesioned hemisphere.

Investigating mechanisms behind offset analgesia: Effect on spinal responses during thermal stimulation

Abstract Introduction Offset analgesia (OA) is a temporal perceptual mechanism in which subjective pain ratings decrease disproportionally when a noxious heat stimulus is decreased by 1–3 ◦C. Whether OA is a peripheral, spinal or supraspinal mechanism remains unknown. The stimulation of afferent nociceptors in the foot, leads to a spinal nociceptive withdrawal reflex (NWR) which is mediated through the wide dynamic range (WDR) neurons and therefore under descending control. We hypothesized that OA affects the spinal nociceptive neurons resulting in an attenuation of the NWR during OA. Methods Four heat stimulations profiles were applied to the lower legs divided into four segments of 5 s, 5 s, 5 s, and 15 s, respectively: Offset Analgesia Trial (OAT) (48, 49, 48, 48 ◦C), Offset Baseline Trial (OBT) (48, 49, 32, 32 ◦C), Constant Heat Trial (CHT) (4 × 48 ◦C), and Baseline Trial (BT) (4 × 32 ◦C). Subjects rated the pain intensity continuously using a visual analog scale (VAS). NWR were evoked by electrical stimulation of the plantar foot and assessed once during each segment by recording EMG from the tibialis anterior muscle. Results VAS-ratings were lower during the third period of OAT compared to CHT (p &lt; 0.001). However, there was no difference (p &gt; 0.05) comparing the NWR size between OAT, OBT, CHT, and BT throughout the time periods. Conclusions The NWR was not affected by OA suggesting that spinal WDR plays a limited role in the OA mechanism. Whether peripheral- or supraspinal mechanisms are responsible the OA phenomenon remains unknown.

Neonatal capsaicin treatment in rats affects TRPV1-related noxious heat sensation and circadian body temperature rhythm

The transient receptor potential vanilloid 1 (TRPV1) is a cation channel that serves as a polymodal detector of noxious stimuli such as capsaicin. Therefore, capsaicin treatment has been used to investigate the physiological function of TRPV1. Here, we report physiological changes induced by treating neonatal rats with capsaicin. Capsaicin (50mg/kg) (cap-treated) or vehicle (vehicle-treated) was systemically administered to newborn SD rat pups within 48h after birth. TRPV1 expression, intake volume of capsaicin water, and noxious heat sensation were measured 6weeks after capsaicin treatment. Circadian body temperature and locomotion were recorded by biotelemetry. Expression of Per1, Per2, Bmal1 and Hsf1 (clock genes) was also investigated. Neonatal capsaicin treatment not only decreased TRPV1 expression but also induced desensitization to noxious heat stimuli. Circadian body temperature of cap-treated rats increased significantly compared with that of vehicle-treated rats. Additionally, the amplitude of the circadian body temperature was reversed in cap-treated rats. Expression of the hypothalamic Hsf1 and liver Per2 clock genes followed a similar trend. Therefore, we suggest that these findings will be useful in studying various physiological mechanisms related to TRPV1.

The rubber hand illusion increases heat pain threshold

Accumulating evidence shows that manipulations of cortical body representation, for example, by simply viewing one's own body, can relieve pain in healthy subjects. Despite the widespread use of the rubber hand illusion (RHI) as an effective experimental tool for the manipulation of bodily awareness, previous studies examining the analgesic effect of the RHI have produced conflicting results. We used noxious heat stimuli to induce finger pain in 29 healthy subjects, and we recorded the participants' pain thresholds and subjective pain ratings during the RHI and during the control conditions. Two control conditions were included in our experiment - a standard one with reduced illusion strength (asynchronous stroking control) and an additional one in which the participants viewed their own hand. Raw data showed that both the RHI and the vision of the own hand resulted in slightly higher pain thresholds than the asynchronous stroking control (illusion: 47.79 °C; own-hand: 47.99 °C; asynchronous: 47.52 °C). After logarithmic transformation to achieve normality, paired t-tests revealed that both increases in pain threshold were significant (illusion/asynchronous: p = 0.036; own-hand/asynchronous: p = 0.007). In contrast, there was no significant difference in pain threshold between the illusion and the own-hand conditions (p = 0.656). Pain rating scores were not log-normal, and Wilcoxon singed-rank tests found no significant differences in pain ratings between the study conditions. The RHI increases heat pain threshold and the analgesic effect of the RHI is comparable with that of seeing one's own hand. The latter finding may have clinical implications.

Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain

Insomnia, depression, and anxiety disorder are common problems for people with neuropathic pain. In this study, mild noxious heat stimuli increased the duration and number of spontaneous pain-like behaviors in sciatic nerve-ligated mice. We used functional magnetic resonance imaging to visualize the increased blood oxygenation level-dependent signal intensity in the anterior cingulate cortex (ACC) of mice with sciatic nerve ligation under mild noxious stimuli. Such stimuli significantly increased the release of glutamate in the ACC of nerve-ligated mice. In addition, sciatic nerve ligation and mild noxious stimuli changed the morphology of astrocytes in the ACC. Treatment of cortical astrocytes with glutamate caused astrocytic activation, as detected by a stellate morphology. Furthermore, glutamate induced the translocation of GAT-3 to astrocyte cell membranes using primary cultured glial cells from the mouse cortex. Moreover, the GABA level at the synaptic cleft in the ACC of nerve-ligated mice was significantly decreased exposure to mild noxious stimuli. Finally, we investigated whether astrocytic activation in the ACC could directly mediate sleep disorder. With the optogenetic tool channel rhodopsin-2 (ChR2), we demonstrated that selective photostimulation of these astrocytes in vivo triggered sleep disturbance. Taken together, these results suggest that neuropathic pain-like stimuli activated astrocytes in the ACC and decreased the extracellular concentration of GABA via an increase in the release of glutamate. Furthermore, these findings provide novel evidence that astrocytic activation in the ACC can mimic sleep disturbance in mice.

Does exercise induce hypoalgesia through conditioned pain modulation?

Pain sensitivity decreases with exercise. The mechanisms that underlie this exercise-induced hypoalgesia (EIH) are unclear. Our purpose was to investigate conditioned pain modulation (CPM) as a potential mechanism of EIH. Sixteen women completed pain testing during three sessions: painful exercise, nonpainful exercise, and quiet rest. Intensity and unpleasantness ratings to noxious heat stimuli were assessed at baseline and during and following each session. Results showed that pain sensitivity decreased significantly during both exercise sessions (p < .05), but not during quiet rest. Effect size calculations showed that the size of the hypoalgesic response was greater following painful exercise than nonpainful exercise. Our results suggest that exercise-induced muscle pain may contribute to the magnitude of EIH. However, as pain sensitivity also decreased following nonpainful exercise, CPM is not likely the primary mechanism of EIH.

Effects of gabapentin on thermal sensitivity following spinal nerve ligation or spinal cord compression

Neuropathic pain challenges healthcare professionals and researchers to develop new strategies of treatment and experimental models to better understand the pathophysiology of this condition. In the present study, the efficacy of gabapentin on thermal sensitivity following spinal nerve ligation and spinal cord compression was evaluated. The method of behavioral assessment was a well-validated cortically dependent operant escape task. Spinal nerve ligation produced peripheral neuropathic pain whereas spinal cord compression, achieved with an expanding polymer placed extradurally, produced a condition of central neuropathic pain. Changes in thermal sensitivity were also observed in animals undergoing nerve ligation surgery without nerve injury. Gabapentin (50 and 100 mg/kg) significantly reduced thermal sensitivity to 10 and 44.5 °C in surgically naive animals as well as those undergoing spinal nerve ligation and spinal cord compression. In conclusion, an operant method of behavioral assessment was used to show that spinal nerve ligation and spinal cord compression produced increases in sensitivity to noxious cold and heat stimuli. A decrease in thermal sensitivity was observed following administration of gabapentin. The results achieved with these methods are consistent with the clinical profile of gabapentin in treating conditions of neuropathic pain.