Pain-induced Changes Research Articles

Multiple Neural Networks Originating from the Lateral Parabrachial Nucleus Modulate Cough-like Behavior and Coordinate Cough with Pain.

It has been reported that experimental pain could diminish cough sensitivity, the lateral parabrachial nucleus (LPBN) coordinated pain with breathing, whether LPBN regulates cough-like behaviors and pain-induced changes in cough sensitivity remains elusive. We investigated the roles of LPBN γ-aminobutyric acidergic (GABAergic) and glutamatergic neurons in the regulation of cough sensitivity and its relationship with pain in mice via chemogenetic approaches. Adeno-associated virus (AAV) tracing combined with chemogenetics was used to map the projections of LPBN GABAergic and glutamatergic neurons to the periaqueductal gray (PAG). LPBN neurons were activated by cough challenge, and nonspecific inhibition of LPBN neurons suppressed cough-like behavior. Chemogenetic suppression of LPBN GABAergic neurons reduced cough sensitivity in mice, whereas suppression of LPBN glutamatergic neurons counteracted the pain-driven decrease in cough sensitivity, so did silencing LPBN glutamatergic neurons projecting to the PAG. Our data suggest that GABAergic and glutamatergic neurons in the LPBN critically are involved in cough sensitivity and coordinate pain with cough through inhibitory or activating mechanisms at the midbrain level.

Relation Between Abnormal Spontaneous Brain Activity and Altered Neuromuscular Activation of Lumbar Paraspinal Muscles in Chronic Low Back Pain

ObjectiveTo investigate the neural mechanism underlying functional reorganization and motor coordination strategies in patients with chronic low back pain (cLBP). DesignA case-control study based on data collected during routine clinical practice. SettingThis study was conducted at a university hospital. ParticipantsFifteen patients with cLBP and 15 healthy controls. InterventionsNot applicable. Main Outcome MeasuresWhole brain blood oxygen level-dependent signals were measured using functional magnetic resonance imaging and amplitude of low-frequency fluctuation (ALFF) method to identify pain-induced changes in regional spontaneous brain activity. A novel approach based on the surface electromyogram (EMG) system and fine-wire electrodes was used to record EMG signals in the deep multifidus, superficial multifidus, and erector spinae. ResultsIn cLBP, compared with healthy groups, ALFF was higher in the medial prefrontal, primary somatosensory, primary motor, and inferior temporal cortices, whereas it was lower in the cerebellum and anterior cingulate and posterior cingulate cortices. Furthermore, the decrease in the average EMG activity of the 3 lumbar muscles in the cLBP group was positively correlated with the ALFF values of the primary somatosensory cortex, motor cortex, precuneus, and middle temporal cortex but significantly negatively correlated with the ALFF values of the medial prefrontal and inferior temporal cortices. Interestingly, the correlation between the functional activity in the cerebellum and the EMG activity varied in the lumbar muscles. ConclusionsThese findings suggest a functional association between changes in spontaneous brain activity and altered voluntary neuromuscular activation patterns of the lumbar paraspinal muscles, providing new insights into the mechanisms underlying pain chronicity as well as important implications for developing novel therapeutic targets of cLBP.

Investigating Whether a Combination of Electro-Encephalography and Gene Expression Profiling Can Predict the Risk of Chronic Pain: A Protocol for an Observational Prospective Cohort Study.

Despite most episodes of low back pain (LBP) being short-lasting, some transition into persistent long-lasting problems. Hence, the need for a deeper understanding of the physiological mechanisms of this is pertinent. Therefore, the aims of the present study are (1) to map pain-induced changes in brain activity and blood gene expression associated with persistent LBP, and (2) to explore whether these brain and gene expression signatures show promise as predictive biomarkers for the development of persistent LBP. The participants will be allocated into three different pain groups (no pain, mild short-lasting, or moderate long-term). One in-person visit, where two blood samples will be collected and sent for RNA sequencing, along with resting 64-channel electro-encephalography measurements before, during, and after a cold pressor test, will be conducted. Thereafter, follow-up questionnaires will be distributed at 2 weeks, 3 months, and 6 months. Recruitment will start during the second quarter of 2024, with expected completion by the last quarter of 2024. The results are expected to provide insight into the relationship between central nervous system activity, gene expression profiles, and LBP. If successful, this study has the potential to provide physiological indicators that are sensitive to the transition from mild, short-term LBP to more problematic, long-term LBP.

Living with non-cardiac chest pain - An inductive qualitative interview study of spouses' perspectives.

To explore spouses' experiences of living with a partner suffering from non-cardiac chest pain (NCPP). An inductive qualitative study. Individual interviews (n = 10) were performed with spouses of partners having NCCP and cardiac anxiety. The analysis was performed according to Patton's guide for content analysis of qualitative data. Three categories and seven subcategories were identified. First, 'a feeling of being neglected', where spouses felt ignored by healthcare professionals and excluded by their partners. Secondly, 'a tension between hope and despair' encompassed feelings of faith, support, unpreparedness for chest pain and situational frustration. Lastly, in 'a threat to ordinary life', spouses noted chest pain-induced changes impacting daily life, finances, leisure and relationships. To conclude, NCCP in partners significantly affects their spouses emotionally and practically. Spouses felt neglected and isolated, oscillating between hope and despair and experiencing faith, powerlessness and frustration. They also faced challenges in daily life and relationships.

The influence of pain and kinesiophobia on motor control of the upper limb: how pointing task paradigms can point to new avenues of understanding.

People experiencing kinesiophobia are more likely to develop persistent disabilities and chronic pain. However, the impact of kinesiophobia on the motor system remains poorly understood. We investigated whether kinesiophobia could modulate shoulder pain-induced changes in (1) kinematic parameters and muscle activation during functional movement and (2) corticospinal excitability. Thirty healthy, pain-free subjects took part in the study. Shoulder, elbow, and finger kinematics, as well as electromyographic activity of the upper trapezius and anterior deltoid muscles, were recorded while subjects performed a pointing task before and during pain induced by capsaicin at the shoulder. Anterior deltoid cortical changes in excitability were assessed through the slope of transcranial magnetic stimulation input-output curves obtained before and during pain. Results revealed that pain reduced shoulder electromyographic activity and had a variable effect on finger kinematics, with individuals with higher kinesiophobia showing greater reduction in finger target traveled distance. Kinesiophobia scores were also correlated with the changes in deltoid corticospinal excitability, suggesting that the latter can influence motor activity as soon as the motor signal emerges. Taken together, these results suggest that pain and kinesiophobia interact with motor control adaptation.

Mirror Therapy Reduces Pain and Preserves Corticomotor Excitability in Human Experimental Skeletal Muscle Pain.

Approaches to preserve corticomotor excitability (CE) are attracting interest as a treatment for pain-induced changes in neural plasticity. We determined the effects of mirror therapy (MT) on skeletal muscle pain. Fifteen healthy adults who received hypertonic saline injections (5.8% NaCl, 0.2 mL) into the first dorsal interosseous (FDI) muscle of the right hand to induce experimental skeletal muscle pain were assigned to either the "MT and injection" or "injection only" group. Post-injection, the "MT and injection" group observed their left index finger abducting and adducting for 4 min, creating the illusion that the right index finger was moving. The "injection only" group remained at rest. CE and pain were assessed by measuring motor-evoked potentials (MEPs) of the right FDI triggered by transcranial magnetic stimulation and the numerical rating scale (NRS), respectively. MEP amplitudes were significantly higher in the "MT and injection" group, a trend that persisted post-MT intervention (MT intervention; p < 0.01, post-1; p < 0.05). The time for the NRS score to reach 0 was notably shorter in the "MT and injection" group (p < 0.05). Our preliminary results suggested that MT decreases CE and pain in skeletal muscles, potentially preventing neural plasticity changes associated with skeletal muscle pain and providing early pain relief.

A neural circuit associated with anxiety-like behaviors induced by chronic inflammatory pain and the anxiolytic effects of electroacupuncture.

Negative emotions induced by chronic pain are a serious clinical problem. Electroacupuncture (EA) is a clinically proven safe and effective method to manage pain-related negative emotions. However, the circuit mechanisms underlying the effect of EA treatment on negative emotions remain unclear. Plantar injection of complete Freund's adjuvant (CFA) was performed to establish a rat model of chronic inflammatory pain-induced anxiety-like behaviors. Adeno-associated virus (AAV) tracing was used to identify excitatory synaptic transmission from the rostral anterior cingulate cortex (rACC) to the dorsal raphe nucleus (DRN). Employing chemogenetic approaches, we examined the role of the rACC-DRN circuit in chronic pain-induced anxiety-like behaviors and investigated whether EA could reverse chronic pain-induced dysfunctions of the rACC-DRN circuit and anxiety-like behaviors. We found that chemogenetic activation of the rACC-DRN circuit alleviated CFA-induced anxiety-like behaviors, while chemogenetic inhibition of the rACC-DRN circuit resulted in short-term CFA-induced anxiety-like behaviors. Further research revealed that the development of CFA-induced anxiety-like behaviors was attributed to the dysfunction of rACC CaMKII neurons projecting to DRN serotonergic neurons (rACCCaMKII-DRN5-HT neurons) but not rACC CaMKII neurons projecting to DRN GABAergic neurons (rACCCaMKII-DRNGABA neurons). This is supported by the findings that chemogenetic activation of the rACCCaMKII-DRN5-HT circuit alleviates anxiety-like behaviors in rats with chronic pain, whereas neither chemogenetic inhibition nor chemogenetic activation of the rACCCaMKII-DRNGABA circuit altered CFA chronic pain-evoked anxiety-like behaviors in rats. More importantly, we found that EA could reverse chronic pain-induced changes in the activity of rACC CaMKII neurons and DRN 5-HTergic neurons and that chemogenetic inhibition of the rACCCaMKII-DRN5-HT circuit blocked the therapeutic effects of EA on chronic pain-induced anxiety-like behaviors. Our data suggest that the reversal of rACCCaMKII-DRN5-HT circuit dysfunction may be a mechanism underlying the therapeutic effect of EA on chronic pain-induced anxiety-like behaviors.

Peak alpha frequency as a candidate biomarker of pain sensitivity: the importance of distinguishing slow from slowing

The study by Valentini et al. (2022) observed that the peak alpha frequency (PAF) of participants became slower after they were exposed to painful, as well as non-painful but unpleasant stimuli. The authors interpreted this as a challenge to our previous studies which propose that the speed of resting PAF, independently of pain-induced changes to PAF, can be a reliable biomarker marker for gaging individual pain sensitivity. While investigations into the role that PAF plays in pain perception are timely, we have some concerns about the assumptions and methodology employed by Valentini et al. Moreover, we believe the authors here have also misrepresented some of our previous work. In the current commentary, we detail the critical differences between our respective studies, with the ultimate aim of guiding future investigations.

Delay and Effort-Based Discounting, and the Role of Bodily Awareness, In People Experiencing Long-Term Pain: A Cross-Sectional Study

Pain interventions typically include effortful exercise and long-term treatment – ie, short-term costs (effort) with delayed benefit (improved pain and/or function). Thus, understanding if long-term pain influences decision-making in context of delays and effort is essential given clear relevance to treatment uptake and/or adherence. We evaluated delay and effort attitudes in those experiencing chronic pain (n = 391) and in pain-free controls (n = 263). Additionally, we investigated the role of bodily sensation awareness and/or interpretation as potential contributing factors to altered decision-making. Volunteers completed three discounting questionnaires, assessing the influence of temporal delays (gains, losses) and effort on devaluation of monetary outcomes. Individuals with chronic pain had more short-sighted decisions for monetary gains, but not losses, and decreased willingness to undertake effort for monetary gains than the No Pain group. The Pain group had higher bodily sensation awareness and while this related to higher impulsivity, delay and effort discounting, neither awareness nor interpretation of bodily sensations interacted with pain levels or explained group differences in discounting behavior. These findings suggest that impaired delay and effort-based discounting is present in people with chronic pain, and that this may be driven by pain-induced changes, but not pain-induced enhancements in bodily sensation awareness and/or interpretation. Exploring the utility of interventions targeting discounting behavior is warranted.Data availability: Study materials are available here: https://osf.io/zexm7/?view_only=c9848597361c41808c612874da6f33b7. PerspectivePeople with chronic pain make more short-sighted decisions (prefer less reward sooner) and decreased willingness to undertake effort (prefer less reward with little effort) for monetary gains than people without pain. Interventions targeting discounting behavior may help improve both uptake and adherence for evidence-based, effortful treatments, such as exercise.

Sex differences in pain-induced modulation of corticotropin-releasing hormone neurons in the dorsolateral part of the stria terminalis in mice

We earlier reported female-biased, sex-specific involvement of the dorsolateral bed nucleus of the stria terminalis (dl BST) in the formalin-induced pain response in rats. The present study investigated pain effects on mice behaviors. Because the dl BST is densely populated with corticotropin-releasing hormone (CRH) neurons, we examined sex differences in these parameters for the dl BST CRH neurons in male and female mice of a mouse line for which the CRH gene promoter (corticotropin-releasing factor [CRF]-Venus ΔNeo) controls the expression of the modified yellow fluorescent protein (Venus).Approximately 92% of Venus-positive cells in the dl BST were also CRH mRNA-positive, irrespective of sex. Therefore, the cells identified using Venus fluorescence were regarded as CRH neurons. A female-biased sex difference was observed in pain-induced behaviors during the interphase (5–15 min after formalin injection) but not during the later phase (phase 2, 15–60 min) in wild-type mice. In CRF-Venus ΔNeo mice, a female-biased difference was observed in either the earlier phase (phase 1, 0–5 min) or the interphase, but not in phase 2. Patch-clamp recordings taken using an acute BST slice obtained from a CRF-Venus ΔNeo mouse after formalin injection showed miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). Remarkably, the mEPSCs frequency was higher in the Venus-expressing cells of formalin-injected female mice than in vehicle-treated female mice. Male mice showed no increase in mEPSC frequency by formalin injection. Formalin injection had no effect on mEPSC or mIPSC amplitudes in either sex. Pain-induced changes in mEPSC frequency in putative CRH neurons were phase-dependent. Results show that excitatory synaptic inputs to BST CRH neurons are temporally enhanced along with behavioral sex differences in pain response, suggesting that pain signals alter the BST CRH neurons excitability in a sex-dependent manner.

Pain-induced changes in motor unit discharge depend on recruitment threshold and contraction speed.

At high forces, the discharge rates of lower- and higher-threshold motor units (MU) are influenced in a different way by muscle pain. These differential effects may be particularly important for performing contractions at different speeds since the proportion of lower- and higher-threshold MUs recruited varies with contraction velocity. We investigated whether MU discharge and recruitment strategies are differentially affected by pain depending on their recruitment threshold (RT), across a range of contraction speeds. Participants performed ankle dorsiflexion sinusoidal-isometric contractions at two frequencies (0.25 and 1 Hz) and two modulation amplitudes [5% and 10% of the maximum voluntary contraction (MVC)] with a mean target torque of 20%MVC. High-density surface electromyography recordings from the tibialis anterior muscle were decomposed and the same MUs were tracked across painful (hypertonic saline injection) and nonpainful conditions. Torque variability, mean discharge rate (MDR), DR variability (DRvar), RT, and the delay between the cumulative spike train and the resultant torque output (neuromechanical delay, NMD) were assessed. The average RT was greater at faster contraction velocities (P = 0.01) but was not affected by pain. At the fastest contraction speed, torque variability and DRvar were reduced (P < 0.05) and MDR was maintained. Conversely, MDR decreased and DRvar and NMD increased significantly during pain at slow contraction speeds (P < 0.05). These results show that reductions in contraction amplitude and increased recruitment of higher-threshold MUs at fast contraction speeds appear to compensate for the inhibitory effect of nociceptive inputs on lower-threshold MUs, allowing the exertion of fast submaximal contractions during pain.NEW & NOTEWORTHY Pain induces changes in motor performance, motor unit recruitment, and rate coding behavior that varies across different contraction speeds. Here we show that that pain reduces motor unit discharge rate and prolongs the neuromechanical delay at slow contraction speeds only. This new evidence suggests that there are differential nociceptive inhibitory effects across the motor unit pool, which allows fast submaximal contractions to be exerted despite the presence of pain.

Pain-induced impulsivity is sexually dimorphic and mu-opioid receptor sensitive in rats.

Pain sensation can negatively impact cognitive function, including impulsivity. Pain-induced changes in impulsivity can contribute to development of psychiatric comorbidities found in those with chronic pain conditions. The goal of this study was to determine whether complete Freund's adjuvant (CFA)-induced pain manipulation enhances impulsivity in rats. Whether the pain-induced impulsivity is sexually dimorphic, and if mu-opioid receptors play a role in these processes. Male and female rats were screened for trait impulsivity and designated as high or low impulsive using a delay discounting task. Rats then received a hind paw injection of CFA, and their impulsivity was assessed for 16days. The effects of morphine on impulsivity were also examined. In a separate experiment, rats were pretreated with beta-funaltrexamine (β-FNA) to determine the role of mu-opioid receptors on impulsivity. CFA treatment increased impulsivity in males and females. The onset of CFA-induced impulsivity was faster in high impulsive females than males. Morphine blocked CFA-induced impulsivity in both sexes in a dose- and time-dependent manner. β-FNA prevented the actions of morphine on CFA-induced impulsivity in high impulsive males, but not high impulsive females. Moreover, β-FNA increased CFA-induced impulsivity in morphine naïve males, but not females. These findings demonstrate unique sex differences in CFA-induced impulsivity, response to morphine, and the impact of mu-opioid receptors. A better understanding of cognitive deficits and their mechanisms can provide insight into the development of substance abuse and psychiatric comorbidities that occur in people with chronic pain.

Effects of inflammatory pain on CB1 receptor in the midbrain periaqueductal gray.

The periaqueductal gray (PAG) mediates the antinociceptive properties of analgesics, including opioids and cannabinoids. Administration of either opioids or cannabinoids into the PAG induces antinociception. However, most studies characterizing the antinociceptive properties of cannabinoids in the PAG have been conducted in naive animals. Few studies have reported on the role of CB1 receptors in the PAG during conditions which would prompt the administration of analgesics, namely, during pain states. To examine inflammatory pain-induced changes in CB1 receptor expression and function in the midbrain periaqueductal gray. In this study, we used the Complete Freund Adjuvant model to characterize CB1 receptor expression and G-protein coupling during persistent inflammatory pain. Inflammatory pain induced an upregulation in the expression of synaptic CB1 receptors in the PAG. Despite this pain-induced change in CB1 expression, there was no corresponding upregulation of CB1 mRNA after the induction of inflammatory pain, suggesting a pain-induced recruitment of CB1 receptors to the synaptic sites within PAG neurons or increased coupling efficiency between the receptor and effector systems. Inflammatory pain also enhanced ventrolateral PAG CB1 receptor activity, as there was an increase in CP55,940-stimulated G-protein activation compared with pain-naïve control animals. These findings complement a growing body of evidence which demonstrate pain-induced changes in brain regions that are responsible for both the analgesic and rewarding properties of analgesic pharmacotherapies. Because much of our understanding of the pharmacology of cannabinoids is based on studies which use largely pain-naïve male animals, this work fills in important gaps in the knowledge base by incorporating pain-induced adaptations and cannabinoid pharmacology in females.

Pain‐induced aggression and changes in social behavior in mice

The effects of neuropathic, formalin, and acetic acid-induced visceral pain were investigated on the social and aggressive behaviors in the Swiss male mice. Neuropathic pain was induced by tibial nerve transection (TNT). Also, somatic and visceral pain was conducted by intraplantar injection of diluted formalin (1%, 20 μl) and intraperitoneal administration of acetic acid (0.6%, 200 μl), respectively. Fourteen and twenty one days after the TNT surgery, and also, 1 and 7 days following formalin and acetic acid administration, the three-chambered test was used to determine sociability and preference for social novelty and resident/intruder test was used for the evaluation of the aggressive behaviors. In the sociability phase of the three-chambered test, all the three models of pain did not change the animal's sociability. However, in the social novelty preference phase, the animals in pain showed deficits in social novelty preference by a significant increase in the time spent with the familiar mice compared to the control groups. Also, animals in pain significantly showed more aggressive behaviors like biting and clinching and have much less attack latency in comparison to the control groups. Pain-induced changes in the social novelty preference and aggressive behaviors continued in the neuropathic group until the end of the experiment. However, 7 days following the induction of both formalin and visceral pain, animals' social memory, and aggression almost returned to the standard value. These results suggest that long-lasting pain could lead to social memory impairment and increase aggressive behaviors in mice.

LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain.

Background and Purpose: Sedation and somnolence remain serious adverse effects of the existing analgesics (e.g., pregabalin, duloxetine) for neuropathic pain. The available evidence indicates that serotonin (5-HT), noradrenaline (NE), and dopamine (DA) play important roles in modulating the descending inhibitory pain pathway and sleep–wake cycle. The aim of this work was to test the hypothesis that LPM580098, a novel triple reuptake inhibitor (TRI) of 5-HT, NE, and DA, has analgesic effect, and does not induce significant adverse effects associated with central inhibition, such as sedation and somnolence.Methods: The analgesic activity of LPM580098 was assessed on formalin test and spinal nerve ligation (SNL)-induced neuropathic pain model. Locomotor activity, pentobarbital sodium-induced sleeping and rota-rod tests were also conducted. In vitro binding and uptake assays, and Western blotting were performed to examine the potential mechanisms.Results: LPM580098 suppressed the nocifensive behaviors during phase II of the formalin test in mice. In SNL rats, LPM580098 (16 mg kg−1) inhibited mechanical allodynia, thermal hyperalgesia and hyperexcitation of wide-dynamic range (WDR) neurons, in which the effect of LPM580098 was similar to pregabalin (30 mg kg−1). However, pregabalin altered the spontaneous locomotion, affected pentobarbital sodium-induced sleep, and showed a trend to perform motor dysfunction, which were not induced by LPM580098. Mechanistically, LPM580098 inhibited the uptake of 5-HT, NE, and DA, improved pain-induced changes of the synaptic functional plasticity and structural plasticity possibly via downregulating the NR2B/CaMKIIα/GluR1 and Rac1/RhoA signaling pathways.Conclusion: Our results suggest that LPM580098, a novel TRI, is effective in attenuating neuropathic pain without producing unwanted sedation and somnolence associated with central nervous system (CNS) depressants.

High-mobility group box 1-mediated microglial activation induces anxiodepressive-like behaviors in mice with neuropathic pain

Clinical evidence indicates that major depression is a common comorbidity of chronic pain, including neuropathic pain. However, the cellular basis for chronic pain-mediated major depression remains unclear. High-mobility group box 1 protein (HMGB1) has a key role in innate immune responses and appears to be have a role in mediating diverse disorders, including neuropathic pain and depression. The current study aimed to characterize neuropathic pain-induced changes in affect over time and to determine whether HMGB1 has a role in neuropathic pain-induced changes in affect. Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) in mice. Anxiodepressive-like behaviors in mice were evaluated over 10 weeks, in the social interaction, forced swim, and novelty suppressed feeding tests. Mice developed anxiodepressive-like behavior 6 to 8 weeks after induction of neuropathy. Accompanying anxiodepressive-like behavior, increased HMGB1 protein and microglia activation were observed in frontal cortex at 8 weeks after PSNL. Intracerebroventricular administration of rHMGB1 in naïve mice induced anxiodepressive-like behavior and microglia activation. Blockage of HMGB1 in PSNL mice with glycyrrhizic acid (GZA) or anti-HMGB1 antibody reduced microglia activation and anxiodepressive-like behavior. These results indicate that PSNL-induced anxiodepressive-like behavior is likely mediated by HMGB1. Furthermore, the data indicate that inhibition of HMGB1-dependent microglia activation could be a strategy for the treatment of depression associated with neuropathic pain.

The central amygdala to periaqueductal gray pathway comprises intrinsically distinct neurons differentially affected in a model of inflammatory pain.

The central nucleus of the amygdala (CeA) encompasses the main output pathways of the amygdala, a temporal lobe structure essential in affective and cognitive dimensions of pain. A major population of neurons in the CeA send projections to the periaqueductal gray (PAG), a key midbrain structure that mediates coping strategies in response to threat or stress. CeA-PAG neurons are topographically organized based on their targeted subregion within the PAG. PAG-projecting neurons in the central medial (CeM) and central lateral (CeL) regions of CeA are intrinsically distinct. CeL-PAG neurons are a homogeneous population of intrinsically distinct neurons while CeM-PAG neurons are intrinsically heterogeneous. Membrane properties of distinct CeM-PAG subtypes are altered in the complete Freund's adjuvant model of inflammatory pain. A major population of neurons in the central nucleus of amygdala (CeA) send projections to the periaqueductal gray (PAG), a key midbrain structure that mediates coping strategies in response to threat or stress. While the CeA-PAG pathway has proved to be a component of descending anti-nociceptive circuitry, the functional organization of CeA-PAG neurons remains unclear. We identified CeA-PAG neurons in C57BL/6 mice of both sexes using intracranial injection of a fluorescent retrograde tracer into the PAG. In acute brain slices, we investigated the topographical and intrinsic characteristics of retrogradely labelled CeA-PAG neurons using epifluorescence and whole-cell electrophysiology. We also measured changes to CeA-PAG neurons in the complete Freund's adjuvant (CFA) model of inflammatory pain. Neurons in the central lateral (CeL) and central medial (CeM) amygdala project primarily to different regions of the PAG. CeL-PAG neurons consist of a relatively homogeneous population of intrinsically distinct neurons while CeM-PAG neurons are intrinsically heterogeneous. Membrane properties of distinct CeM-PAG subtypes are altered 1day after induction of the CFA inflammatory pain model. Collectively, our results provide insight into pain-induced changes to a specific population of CeA neurons that probably play a key role in the integration of noxious input with endogenous analgesia and behavioural coping response.

The effect of CA1 administration of orexin-A on hippocampal expression of COX-2 and BDNF in a rat model of orofacial pain.

The neuropeptide orexin-A and its receptors are widely distributed in both hippocampal circuitry and pain transmission pathways. Involvement of the CA1 orexin 1 receptor (OX1R) on the modulation of orofacial pain and pain-induced changes in hippocampal expression of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) was investigated. Orofacial pain was induced by an intra-lip injection of capsaicin (100 μg). Reverse transcription polymerase chain reaction and immunoblot analysis were used to indicate changes in hippocampal BDNF and COX-2 expression, respectively. Capsaicin induces a significant pain response, which is not affected by either orexin-A or SB-334867-A, an OX1R antagonist. However, an increased expression of COX-2 and decreased expression of BDNF was observed in the hippocampus of animals that received capsaicin or SB-334867-A (80 nM) plus capsaicin. Meanwhile, orexin-A (40 pM) attenuated the effects of capsaicin on the expression of COX-2 and BDNF. CA1 OX1R activation moderates capsaicin-induced neuronal inflammation and neurotrophic deficiency.

Pain-induced changes in heart rate variability in patients with idiopathic REM sleep behavior disorder

Pain-induced changes in heart rate variability in patients with idiopathic REM sleep behavior disorder

Pain Affects Visual Orientation: an Eye-Tracking Study

Because of its unique evolutionary relevance, it is understood that pain automatically attracts attention. So far, such attentional bias has mainly been shown for pain-related stimuli whereas little is known about shifts in attentional focus after actual painful stimulation. This study investigated attentional shifts by assessing eye movements into the direction of painful stimulation. Healthy participants were presented either a blank screen or a picture showing a natural scene while painful electrical stimuli were applied to the left or right hand. In general, painful stimulation reduced exploratory behavior as reflected by less and slower saccades as well as fewer and longer fixations. Painful stimulation on the right hand induced a rightward bias (ie, increased initial saccades, total number and duration of fixations to the right hemifield of the screen). Pain applied to the left hand as well as no pain induced a leftward bias that was largest for the direction of first saccades. These findings are in line with previous observations of attentional biases toward pain-related information and highlight eye tracking as a valuable tool to assess involuntary attentional consequences of pain. Future studies are needed to investigate how the observed changes in eye movements relate to pain-induced changes in perception and cognition. PerspectiveThe study investigated pain-induced attentional shifts in terms of reflexive eye movements. This attention-capturing quality of pain should be examined in chronic pain conditions because it might contribute to the cognitive impairments often observed in chronic pain patients.