Re-examining the Mysterious Role of the Cerebellum in Pain.

Pain is considered a multidimensional experience that embodies not merely sensation, but also emotion and perception. As is appropriate for this complexity, pain is represented and processed by an extensive matrix of cortical and subcortical structures. Of these structures, the cerebellum is gaining increasing attention. Although association between the cerebellum and both acute and chronic pain have been extensively detailed in electrophysiological and neuroimaging studies, a deep understanding of what functions are mediated by these associations is lacking. Nevertheless, the available evidence implies that lobules IV-VI and Crus I are especially pertinent to pain processing, and anatomical studies reveal that these regions connect with higher-order structures of sensorimotor, emotional, and cognitive function. Therefore, we speculate that the cerebellum exerts a modulatory role in pain via its communication with sites of sensorimotor, executive, reward, and limbic function. On this basis, in this review, we propose numerous ways in which the cerebellum might contribute to both acute and chronic pain, drawing particular attention to emotional and cognitive elements of pain. In addition, we emphasise the importance of advancing our knowledge about the relationship between the cerebellum and pain by discussing novel therapeutic opportunities that capitalize on this association.

Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

Physical fitness in children with Marfan and Loeys-Dietz syndrome: associations between cardiovascular parameters, systemic manifestations, fatigue, and pain.

Children with Marfan (MFS) and Loeys-Dietz syndrome (LDS) report limitations in physical activities, sports, school, leisure, and work participation in daily life. This observational, cross-sectional, multicenter study explores associations between physical fitness and cardiovascular parameters, systemic manifestations, fatigue, and pain in children with MFS and LDS. Forty-two participants, aged 6-18 years (mean (SD) 11.5(3.7)), diagnosed with MFS (n = 36) or LDS (n = 6), were enrolled. Physical fitness was evaluated using the Fitkids Treadmill Test's time to exhaustion (TTE) outcome measure. Cardiovascular parameters (e.g., echocardiographic parameters, aortic surgery, cardiovascular medication) and systemic manifestations (systemic score of the revised Ghent criteria) were collected. Pain was obtained by visual analog scale. Fatigue was evaluated by PROMIS® Fatigue-10a-Pediatric-v2.0-short-form and PROMIS® Fatigue-10a-Parent-Proxy-v2.0-short-form. Multivariate linear regression analyses explored associations between physical fitness (dependent variable) and independent variables that emerged from the univariate linear regression analyses (criterion p < .05). The total group (MFS and LDS) and the MFS subgroup scored below norms on physical fitness TTE Z-score (mean (SD) -3.1 (2.9); -3.0 (3.0), respectively). Univariate analyses showed associations between TTE Z-score aortic surgery, fatigue, and pain (criterion p < .05). Multivariate analyses showed an association between physical fitness and pediatric self-reported fatigue that explained 48%; 49%, respectively, of TTE Z-score variance (F (1,18) = 18.6, p ≤ .001, r2 = .48; F (1,15) = 16,3, p = .01, r2 = .49, respectively).    Conclusions: Physical fitness is low in children with MFS or LDS and associated with self-reported fatigue. Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with MFS and LDS. What is Known: • Marfan and Loeys-Dietz syndrome are heritable connective tissue disorders and share cardiovascular and systemic manifestations. • Children with Marfan and Loeys-Dietz syndrome report increased levels of disability, fatigue and pain, as well as reduced levels of physical activity, overall health and health-related quality of life. What is New: • Physical fitness is low in children with Marfan and Loeys-Dietz syndrome and associated with self-reported fatigue. • Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with Marfan and Loeys-Dietz syndrome.

Evaluating peripheral neuromuscular function with brief movement-evoked pain.

Movement-evoked pain is an understudied manifestation of musculoskeletal conditions that contributes to disability, yet little is known about how the neuromuscular system responds to movement-evoked pain. The present study examined whether movement-evoked pain impacts force production, electromyographic (EMG) muscle activity, and the rate of force development (RFD) during submaximal muscle contractions. Fifteen healthy adults (9 males; age = 30.3 ± 10.2 yr, range = 22-59 yr) performed submaximal isometric first finger abduction contractions without pain (baseline) and with movement-evoked pain induced by laser stimulation to the dorsum of the hand. Normalized force (% maximal voluntary contraction) and RFD decreased by 11% (P < 0.001) and 15% (P = 0.003), respectively, with movement-evoked pain, without any change in normalized peak EMG (P = 0.77). Early contractile RFD, force impulse, and corresponding EMG amplitude computed within time segments of 50, 100, 150, and 200 ms relative to the onset of movement were also unaffected by movement-evoked pain (P > 0.05). Our results demonstrate that movement-evoked pain impairs peak characteristics and not early measures of submaximal force production and RFD, without affecting EMG activity (peak and early). Possible explanations for the stability in EMG with reduced force include antagonist coactivation and a reorganization of motoneuronal activation strategy, which is discussed here.NEW & NOTEWORTHY We provide neurophysiological evidence to indicate that peak force and rate of force development are reduced by movement-evoked pain despite a lack of change in EMG and early rapid force development in the first dorsal interosseous muscle. Additional evidence suggests that these findings may coexist with a reorganization in motoneuronal activation strategy.

Effect of wearable chair on gait, balance, and discomfort of new users during level walking with anterior loads.

INTRODUCTION: Walking with anterior loads is common in industrial scenarios, but as exoskeletons are increasingly used in work environments to alleviate musculoskeletal disorders (MSDs), this new "human-robot" system composed of the human body and exoskeleton may be associated with new risks and harm that warrant further investigation. Therefore, this study will discuss the effect of a wearable chair on the gait, balance, and discomfort of new users with different weights of anterior loads during level walking. METHOD: Twenty-two healthy subjects (sex balanced) participated in the experiment. Each exposure comprised one of two exoskeleton states (with/without) and four load conditions: No carried load, carrying an empty box (0.3 kg), 5%Body Weight (BW), and 10%BW. The order of exoskeleton states and load conditions was randomly assigned. Using an eight-camera motion capture system to record the entire movement. And the subjective discomfort and perceived balance after each exposure were recorded on an 11-point numeric rating scale, respectively. Using SPSS 26.0 software (IBM Inc., Chicago) to conduct statistical analyses. RESULTS: Level walking with a wearable chair in different load conditions significantly affected gait parameters (like cadence) and gait balance. The perceived balance decreased with the exoskeleton, consistent with objective results. For subjective discomfort, wearing the exoskeleton significantly impacted global discomfort. Also, it increased the local discomfort of the shoulders, waist, thighs, shanks, and feet/ankles. CONCLUSIONS: For new users, the risk of losing balance or falling may be increased when wearing an exoskeleton for non-target task behaviors (level walking/anterior load), and caution is recommended when the anterior load exceeds 5% BW. PRACTICAL APPLICATION: The proposed strategy for assessing human gait, balance, and discomfort in wearable chairs may be applied during the iterative design of the product. These controls will help develop training programs and implementation guidelines for this exoskeleton type.

Correlations between within-subject variability of pain intensity reports and rubber hand illusion proprioceptive drift.

INTRODUCTION: Consistent with the Bayesian brain hypothesis, the within-subject variability of pain intensity reports as captured with the Focused Analgesia Selection Test (FAST) might be a surrogate measure of the certainty in ascending noxious signals. The outcomes of a non-pain-related task, the rubber hand illusion, were hypothesized to reflect the same construct. This study aimed to explore whether within-subject differences in variability of pain intensity reports and the outcomes of the rubber hand illusion might be related. METHODS: Nonclinical participants underwent the classic rubber hand illusion under synchronous (experimental) and asynchronous (control) conditions. Two outcomes were assessed: proprioceptive drift and feeling of ownership. Thereafter, participants underwent the FAST to assess the within-subject variability of pain reports in response to heat stimuli. Intraclass correlation (ICC) and the correlation coefficient (R2) were the main outcomes. Spearman's correlations were used to assess associations between the outcomes of the 2 tasks. RESULTS: Thirty-six volunteers completed the study. Both FAST outcomes-ICC (Spearman's r = 0.355, p = 0.033) and R2 (Spearman's r = 0.349, p = 0.037)-were positively correlated with proprioceptive drift in the synchronous but not asynchronous conditions (p > 0.05). The subjective feeling of ownership and FAST outcomes did not correlate (p > 0.05). CONCLUSIONS: The associations between the 2 tasks' outcomes imply that both tasks at least partly assess similar constructs. Current knowledge suggests that this construct represents the person's certainty in perceiving ascending sensory signals, or, in Bayesian terminology, the certainty of the likelihood.

PKA mediates modality-specific modulation of the mechanically gated ion channel PIEZO2.

PKA is a downstream effector of many inflammatory mediators that induce pain hypersensitivity by increasing the mechanosensitivity of nociceptive sensory afferent. Here, we examine the molecular mechanism underlying PKA-dependent modulation of the mechanically activated ion channel PIEZO2, which confers mechanosensitivity to many nociceptors. Using phosphorylation site prediction algorithms, we identified multiple putative and highly conserved PKA phosphorylation sites located on intracellular intrinsically disordered regions of PIEZO2. Site-directed mutagenesis and patch-clamp recordings showed that substitution of one or multiple putative PKA sites within a single intracellular domain does not alter PKA-induced PIEZO2 sensitization, whereas mutation of a combination of nine putative sites located on four different intracellular regions completely abolishes PKA-dependent PIEZO2 modulation, though it remains unclear whether all or just some of these nine sites are required. By demonstrating that PIEZO1 is not modulated by PKA, our data also reveal a previously unrecognized functional difference between PIEZO1 and PIEZO2. Moreover, by demonstrating that PKA only modulates PIEZO2 currents evoked by focal mechanical indentation of the cell, but not currents evoked by pressure-induced membrane stretch, we provide evidence suggesting that PIEZO2 is a polymodal mechanosensor that engages different protein domains for detecting different types of mechanical stimuli.

High intensity-transcutaneous electrical nerve stimulation does not inhibit temporal summation of the nociceptive flexion reflex.

Pain facilitation contributes to chronic pain conditions. Transcutaneous electrical nerve stimulation (TENS) is used to alleviate pain. The effects of conventional TENS on chronic pain have been limited, and its effects on pain facilitation are controversial. Because the analgesic effects of TENS depend on the setting parameters (e.g., pulse intensities or treatment time), the optimal TENS settings to maximize analgesic effects under various pain conditions have been investigated. High-intensity TENS (HI-TENS), which involves tolerable-level pulse intensities for a short duration, is another conventional TENS method that used to alleviate pain. However, the effects of HI-TENS on pain facilitation remain unclear. The temporal summation of pain is widely used to evaluate pain facilitation, and the temporal summation-nociceptive flexion reflex (TS-NFR) is a neuropsychological parameter that can be used to evaluate pain facilitation. We aimed to investigate the effects of HI-TENS on the TS-NFR in healthy participants. Participants were randomly allocated into HI-TENS (n = 15) and control groups (n = 16). HI-TENS was administered at the left lateral lower leg for 1 min. The TS-NFR elicited by three noxious stimuluses at the left sural nerve was obtained from electromyography of the left biceps femoris. The nociceptive flexion reflex (NFR) was obtained by a single noxious stimulus. We measured the thresholds of the NFR and the TS-NFR at baseline and post-intervention. The application of HI-TENS significantly increased the NFR threshold (p = 0.013) but not the TS-NFR threshold (p > 0.05). These results suggest that HI-TENS does not inhibit pain facilitation.

A Latin American consensus meeting on the essentials of mixed pain.

OBJECTIVES: The term "mixed pain" has been established when a mixture of different pain components (e.g. nociceptive, neuropathic, and nociplastic) are present. It has gained more and more acceptance amongst pain experts worldwide, but many questions around the concept of mixed pain are still unsolved. The sensation of pain is very personal. Cultural, social, personal experiences, idiomatic, and taxonomic differences should be taken into account during pain assessment. Therefore, a Latin American consensus committee was formed to further elaborate the essentials of mixed pain, focusing on the specific characteristics of the Latin American population. METHODS: The current approach was based on a systematic literature search and review carried out in Medline. Eight topics about the definition, diagnosis, and treatment of mixed pain were discussed and voted for by a Latin American consensus committee and recommendations were expressed. RESULTS: At the end of the meeting a total of 14 voting sheets were collected. The full consensus was obtained for 21 of 25 recommendations (15 strong agreement and 6 unanimous agreement) formulated for the above described 8 topics (7 of the 8 topics had for all questions at least a strong agreement - 1 topic had no agreement for all 4 questions). CONCLUSION: In a subject as complex as mixed pain, a consensus has been reached among Latin American specialists on points related to the definition and essence of this pain, its diagnosis and treatment. Recommendations for diagnosis and treatment of mixed pain in Latin America were raised.

Structural integrity of corpus callosum in patients with migraine: a diffusion tensor imaging study.

The aim of this study was to compare structural changes of corpus callosum (CC), which is the largest collection of white matter in the brain, among migraineurs and healthy controls (HC). Diffusion tensor imaging (DTI) method which provides information about microscopic organization of the cell, especially white matter was used for this purpose. Fifty-one patients who were diagnosed with migraine and 44 age- and sex-matched HC were included in the study. Socio-demographic and clinical characteristics of the patients were noted. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) measurements of CC genu, splenium, and body were performed for all participants. A significant difference was determined between migraine patients and HC regarding the FA values in the genu of CC (p < 0.001). When the clinical data of migraine patients and FA values in the genu of CC were analyzed via linear regression analysis, no significant finding was detected (p > 0.05). In conclusion, it can be suggested that there are microstructural changes in the CC of migraneurs; however, the clinical variable associated with this structural deterioration could not be determined.

Dolor, uso de ortesis plantares, calzado y consejos de salud en personas con lupus eritematoso sistémico. Un estudio descriptivo / Pain, use of plantar orthoses, footwear and health advice in people with systemic lupus erythematosus. A descriptive study

Objetivos: Conocer la percepción de los pacientes sobre el dolor y localización en los pies debido al lupus eritematoso sistémico (LES). Identificar los consejos y cuidados recibidos sobre los problemas de sus pies y calzado, y qué profesional los proporcionó. Conocer si los pacientes usaban ortesis plantares o calzado ortopédico. Pacientes y métodos: Estudio observacional, descriptivo, transversal, realizado entre marzo y mayo de 2021 sobre 47 personas con LES. Cinco participantes se excluyeron por no completar el cuestionario, siendo 42 los participantes después de obtener su consentimiento informado. Se confeccionó una hoja de recogida de datos para alcanzar los objetivos. Resultados: El 47.6 % de los pacientes presentaba dolor en los pies atribuido al LES durante la entrevista, con un promedio de dolor de 4.4 (DE = 2.97). El dolor se localizó principalmente en el antepié y los dedos. El 31 % y el 21.4 % recibieron cuidados o consejos para sus problemas en los pies respectivamente, siendo podólogos y reumatólogos los principales prescriptores. El 31 % recibió consejos sobre el calzado adecuado, proporcionados principalmente por podólogos y reumatólogos. El 33.33 % utilizaba ortesis plantares, siendo mayormente prescritas por reumatólogos y podólogos. Solo un 4.8 % utilizaba calzado ortopédico o hecho a medida. Conclusiones: Se encontró una prevalencia significativa de dolor en los pies atribuido al LES, siendo el antepié y los dedos las áreas más afectadas. Un porcentaje limitado de pacientes recibió cuidados y consejos para sus problemas en los pies, y el uso de ortesis plantares y calzado ortopédico fue poco común (AU)

Objectives: To know the perception of patients about pain and location in the feet due to Systemic Lupus Erythematosus (SLE). Identify the advice and care received about the problems of your feet and footwear, and which professional provided it. To know if patients wore plantar orthoses or orthopedic shoes. Patients and methods: Observational, descriptive, cross-sectional study, conducted between March and May 2021 on 47 people with SLE. Five participants were excluded for not completing the questionnaire, with 42 participants after obtaining their informed consent. A data collection sheet was prepared to achieve the objectives. Results: A total of 47.6 % of patients had foot pain attributed to SLE during the interview, with an average pain of 4.4 (SD = 2.97). The pain was mainly localized to the forefoot and fingers. Thirtyone (31 %) and 21.4 % received care or advice for their foot problems respectively, with podiatrists and rheumatologists being the main prescribers. Also, 31 % received advice on proper footwear, provided mainly by podiatrists and rheumatologists. One third (33,33 %) used plantar orthoses, being mostly prescribed by rheumatologists and podiatrists. Only 4.8 % used orthopedic or custom-made shoes.Conclusions: A significant prevalence of foot pain attributed to SLE was found, with the forefoot and toes being the most affected areas. A limited percentage of patients received care and advice for their foot problems, and the use of plantar orthotics and orthopedic footwear was uncommon (AU)

Distinct neural networks derived from galanin-containing nociceptors and neurotensin-expressing pruriceptors.

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin (Gal) and one type of pruriceptors expressing neurotensin (Nts). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from Nts-expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the Gal-containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the Nts-expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch.

Pain hypersensitivity in a pharmacological mouse model of attention-deficit/hyperactivity disorder.

Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.

Acupuncture-Induced Changes in Nociception, Measured by Pain-Related Evoked Potentials: A Pilot Mechanistic Study.

Objective: The nociceptive system has been implicated in acupuncture analgesia, although acupuncture's precise mechanism of action remains unknown. Electric pain-related evoked potentials (PREPs) have emerged as an effective and reliable electrophysiologic method for evaluation of the human nociceptive system by electric stimulation of nociceptive Aδ and C fibers. This pilot mechanistic study aims to assess the feasibility of using advanced PREP techniques together with electroacupuncture and to use PREPs to characterize acupuncture's effect on nociception. Methods: Seven healthy volunteers underwent a previously designed electroacupuncture protocol using acupoints in the legs bilaterally, which has been demonstrated to induce systemic analgesia. Advanced PREP techniques involving tripolar stimulating electrode, varying interstimulus interval, and incorporating a cognitive task during PREPs were used. PREPs were assessed before electroacupuncture, during electroacupuncture, and 30 min after electroacupuncture. Subjective pain perception in response to the PREP-related electric pain stimuli delivered to the nondominant hand was assessed on the visual analog scale (VAS) at baseline, during electroacupuncture, and 30 min postelectroacupuncture. Results: Reliable PREP N1, P1, and N2 waves were obtained from all subjects at the following average latencies: N1 = 131.5 msec, P1 = 189.4 msec, and N2 = 231.1 msec. Electroacupuncture caused a significant reduction in PREP N1P1 wave amplitudes from 25.6 to 15.4 µV (p = 0.006) and electric pain perception on the VAS-from 2.86 to 2.14 (p = 0.008), compared to baseline. These effects were sustained at 30 min postacupuncture with N1P1 wave amplitude 17.2 µV (p = 0.030) and VAS 2.28 (p = 0.030), compared to baseline. Conclusions: Electroacupuncture causes significant changes in objective nociception, measured by PREP N1P1 wave amplitudes, and in subjective nociception, measured by the VAS, and these effects are sustained for 30 min after electroacupuncture. Planned future studies will involve chronic pain populations and will aim to assess acupuncture's longer term analgesic effects.

Microglia-mediated degradation of perineuronal nets promotes pain.

Activation of microglia in the spinal cord dorsal horn after peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that after peripheral nerve injury, microglia degrade extracellular matrix structures, perineuronal nets (PNNs), in lamina I of the spinal cord dorsal horn. Lamina I PNNs selectively enwrap spinoparabrachial projection neurons, which integrate nociceptive information in the spinal cord and convey it to supraspinal brain regions to induce pain sensation. Degradation of PNNs by microglia enhances the activity of projection neurons and induces pain-related behaviors. Thus, nerve injury-induced degradation of PNNs is a mechanism by which microglia selectively augment the output of spinal nociceptive circuits and cause pain hypersensitivity.

Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit.

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla contains neurons that robustly inhibit nocioception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the rostral ventromedial medulla in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the rostral ventromedial medulla has never been achieved. We now expose a cellular circuit that inhibits nocioception and itch in mice. Through a combination of molecular, tracing and behavioural approaches, we found that rostral ventromedial medulla neurons containing the kappa-opioid receptor inhibit itch and nocioception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that rostral ventromedial medulla kappa-opioid receptor neurons inhibit nocioception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal grey that modulates nociception within the rostral ventromedial medulla. These discoveries highlight a distinct population of rostral ventromedial medulla neurons capable of broadly and robustly inhibiting itch and nocioception.

Serodolin, a ß-arrestin-biased ligand of 5-HT7 receptor, attenuates pain-related behaviors.

G protein­coupled receptors (GPCRs) are involved in regulation of manifold physiological processes through coupling to heterotrimeric G proteins upon ligand stimulation. Classical therapeutically active drugs simultaneously initiate several downstream signaling pathways, whereas biased ligands, which stabilize subsets of receptor conformations, elicit more selective signaling. This concept of functional selectivity of a ligand has emerged as an interesting property for the development of new therapeutic molecules. Biased ligands are expected to have superior efficacy and/or reduced side effects by regulating biological functions of GPCRs in a more precise way. In the last decade, 5-HT7 receptor (5-HT7R) has become a promising target for the treatment of neuropsychiatric disorders, sleep and circadian rhythm disorders, and pathological pain. In this study, we showed that Serodolin is unique among a number of agonists and antagonists tested: it behaves as an antagonist/inverse agonist on Gs signaling while inducing ERK activation through a ß-arrestin­dependent signaling mechanism that requires c-SRC activation. Moreover, we showed that Serodolin clearly decreases hyperalgesia and pain sensation in response to inflammatory, thermal, and mechanical stimulation. This antinociceptive effect could not be observed in 5-HT7R knockout (KO) mice and was fully blocked by administration of SB269-970, a specific 5-HT7R antagonist, demonstrating the specificity of action of Serodolin. Physiological effects of 5-HT7R stimulation have been classically shown to result from Gs-dependent adenylyl cyclase activation. In this study, using a ß-arrestin­biased agonist, we provided insight into the molecular mechanism triggered by 5-HT7R and revealed its therapeutic potential in the modulation of pain response.