Affective Component Of Pain Research Articles

Analgosedation in Pediatric Emergency Care: A Comprehensive Scoping Review

Effective management of pain and anxiety in pediatric emergency room is crucial for ensuring both the physical and emotional well-being of young patients. Analgosedation, a combination of analgesia and sedation, is commonly used to facilitate various procedures in children. However, selecting the optimal agent and administration route remains challenging due to the unique pharmacological profiles and side effects of available drugs. This scoping review aims to provide a comprehensive analysis of the pharmacological agents used for procedural analgosedation in pediatric emergency settings, focusing on their efficacy, safety, administration routes, and potential side effects. A systematic review of the literature was conducted, focusing on key agents such as ketamine, midazolam, dexmedetomidine, fentanyl, and nitrous oxide. Studies were included based on their relevance to pediatric procedural sedation, particularly in emergency settings. Literature analysis showed that ketamine and fentanyl are effective for managing moderate to severe pain, with a rapid onset of action. Fentanyl is preferred for acute pain management following fractures and burns, while ketamine and midazolam are commonly used for emergency analgosedation. Dexmedetomidine, which induces sedation similar to natural sleep, is particularly effective in preventing pain and agitation during procedures and is well tolerated in children, especially those with developmental disorders. Nitrous oxide, when used in a 50% oxygen mixture, offers a valuable option for conscious sedation during mildly to moderately painful procedures, maintaining respiratory and airway reflexes. No single drug is ideal for all pediatric patients and procedures and the choice of agent should be tailored to the specific clinical scenario, considering both the sensory and affective components of pain. Future research should prioritize large-scale comparative studies, the exploration of combination therapies, and the development of non-pharmacological adjuncts to enhance the safety and efficacy of pediatric analgosedation.

Cingulotomy for Intractable Pain: A Systematic Review of an Underutilized Procedure.

Pain management is a critical aspect of cancer treatment and palliative care, where pain can significantly impact quality of life. Chronic pain, which affects a significant number of people worldwide, remains a prevalent and challenging symptom for patients. While medications and psychosocial support systems play a role in pain management, surgical and radiological interventions, including cingulotomy, may be necessary for refractory cases. Cingulotomy, a neurosurgical procedure targeting the cingulate gyrus, aims to disrupt neural pathways associated with emotional processing and pain sensation, thereby reducing the affective component of pain. Although cingulotomy has shown promise in providing pain relief, particularly in patients refractory to traditional medical treatment, its use has declined in recent years due to advancements in non-destructive therapies and concerns about long-term efficacy and patient suitability. Modern stereotactic methods have enhanced the precision and safety of cingulotomy, reducing associated complications and mortality rates. Despite these advancements, questions remain regarding its long-term efficacy and suitability for patients with limited life expectancy, particularly those with cancer. A comprehensive systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, aimed at providing insights into the efficacy, potential benefits, and limitations of this neurosurgical procedure in managing intractable pain. An electronic search of PubMed, Embase, Scopus, and Web of Science was conducted with open database coverage dates. The review focused on outcomes such as pain intensity and quality of life. The inclusion criteria encompassed human studies of any age experiencing intractable cancer or non-cancer pain, with cingulotomy as the primary intervention. Various study designs were considered, including observational studies, clinical trials, and reviews focusing on pain and cingulotomy. Exclusion criteria included non-human studies, non-peer-reviewed articles, and studies unrelated to pain or cingulotomy. This review highlights the efficacy of stereotactic anterior cingulotomy in managing intractable pain, particularly when conventional treatments fail. Advanced MRI-guided techniques enhance precision, but challenges like cost and expertise persist. Studies included in this review showed significant pain relief with minimal adverse effects, although the optimal target remains debated. Neurocognitive risks exist, but outcomes are generally favorable. Expected adverse events include transient effects like urinary incontinence and confusion. Reoperation may be necessary for inadequate pain control, with a median pain relief duration of three months to a year. A double stereotactic cingulotomy appears to be safe and effective for refractory pain.

Graph theory analysis reveals an assortative pain network vulnerable to attacks

The neural substrate of pain experience has been described as a dense network of connected brain regions. However, the connectivity pattern of these brain regions remains elusive, precluding a deeper understanding of how pain emerges from the structural connectivity. Here, we employ graph theory to systematically characterize the architecture of a comprehensive pain network, including both cortical and subcortical brain areas. This structural brain network consists of 49 nodes denoting pain-related brain areas, linked by edges representing their relative incoming and outgoing axonal projection strengths. Within this network, 63% of brain areas share reciprocal connections, reflecting a dense network. The clustering coefficient, a measurement of the probability that adjacent nodes are connected, indicates that brain areas in the pain network tend to cluster together. Community detection, the process of discovering cohesive groups in complex networks, successfully reveals two known subnetworks that specifically mediate the sensory and affective components of pain, respectively. Assortativity analysis, which evaluates the tendency of nodes to connect with other nodes that have similar features, indicates that the pain network is assortative. Finally, robustness, the resistance of a complex network to failures and perturbations, indicates that the pain network displays a high degree of error tolerance (local failure rarely affects the global information carried by the network) but is vulnerable to attacks (selective removal of hub nodes critically changes network connectivity). Taken together, graph theory analysis unveils an assortative structural pain network in the brain that processes nociceptive information. Furthermore, the vulnerability of this network to attack presents the possibility of alleviating pain by targeting the most connected brain areas in the network.

The pro-resolving lipid mediator Maresin 1 ameliorates pain responses and neuroinflammation in the spared nerve injury-induced neuropathic pain: A study in male and female mice.

Specialized pro-resolving mediators (SPMs) have recently emerged as promising therapeutic approaches for neuropathic pain (NP). We evaluated the effects of oral treatment with the SPM Maresin 1 (MaR1) on behavioral pain responses and spinal neuroinflammation in male and female C57BL/6J mice with spared nerve injury (SNI)-induced NP. MaR1, or vehicle, was administered once daily, on post-surgical days 3 to 5, by voluntary oral intake. Sensory-discriminative and affective-motivational components of pain were evaluated with von Frey and place escape/avoidance paradigm (PEAP) tests, respectively. Spinal microglial and astrocytic activation were assessed by immunofluorescence, and the spinal concentration of cytokines IL-1β, IL-6, IL-10, and macrophage colony-stimulating factor (M-CSF) were evaluated by multiplex immunoassay. MaR1 treatment reduced SNI-induced mechanical hypersensitivity on days 7 and 11 in both male and female mice, and appeared to ameliorate the affective component of pain in males on day 11. No definitive conclusions could be drawn about the impact of MaR1 on the affective-motivational aspects of pain in female mice, since repeated suprathreshold mechanical stimulation of the affected paw in the dark compartment did not increase the preference of vehicle-treated SNI females for the light side, during the PEAP test session (a fundamental assumption for PAEP's validity). MaR1 treatment also reduced ipsilateral spinal microglial and astrocytic activation in both sexes and marginally increased M-CSF in males, while not affecting cytokines IL-1β, IL-6 and IL-10 in either sex. In summary, our study has shown that oral treatment with MaR1 (i) produces antinociception even in an already installed peripheral NP mouse model, and (ii) this antinociception may extend for several days beyond the treatment time-frame. These therapeutic effects are associated with attenuated microglial and astrocytic activation in both sexes, and possibly involve modulation of M-CSF action in males.

The sensory and affective components of pain differentially shape pupillary dilatation during cold pressor tests

Nociceptive and affective stimuli increase reflex sympathetic outflow to the pupils. To investigate effects of stimulus intensity, unpleasantness and distress on these pupillary reflexes, and to assess their stability, healthy participants immersed their hand in ice-water three times (for 20, 40 and 60s; or 60, 40 and 20s; or three times for 60s) (N=21 in each condition). Each ice-water immersion was preceded by a 90s warm water immersion. To evaluate phasic sympathetic influences on pupil diameter, pupillary re-dilatation after 1s of bright light was assessed during the last 10s of each immersion. By-and-large, pain ratings and pupil diameter were greater during longer than shorter ice-water immersions, and ice-water immersions facilitated pupillary re-dilatation after the flash stimulus. However, mean pupil diameter during ice- and warm water immersions, minor ipsilateral amplification of the pupillary response, and ratings of pain unpleasantness and distress decreased across the experiment. Together, these findings suggest that nociceptive input increased sympathetic pupillary tone and amplified phasic increases in sympathetic activity after exposure to light. However, tonic sympathetic influences on pupil diameter and lateralization decreased across repeated immersions, possibly as novel or threatening aspects of the experience declined. Pupillary nociceptive and affective reflexes involve the locus coeruleus, an integral component of neural circuits that heighten cortical arousal and regulate pain. As these reflexes appear to reflect different aspects of sensory and affective processing, their combined assessment might increase the sensitivity and specificity of tests of locus coeruleus function in patients with suspected deficits.

The effect of background liked music on acute pain perception and its neural correlates.

Music shows tremendous promise in pain relief, especially when considering its non-pharmacological nature. However, our understanding of the precise mechanisms behind music-induced analgesia (MIA) remains poor. The positive emotional state induced by music is one of the key components explaining MIA. To test this possibility and reveal its neural correlates, the present study applied nociceptive laser stimuli to 28 healthy participants when their liked or disliked songs were played as background music, or when they were resting in silence. Differences among conditions were quantified by self-reports of pain intensity and unpleasantness, as well as brain activations in response to acute laser stimuli. As expected, liked music significantly lowered pain ratings to acute painful stimuli compared to disliked music and no music. Consistent with this observation, brain activations in response to acute painful stimuli were deceased within brain areas encoding sensory components of pain, such as the right precentral and postcentral gyri (PreCG/PoCG), brain areas related to affective components of pain, such as the anterior cingulate cortex and bilateral putamen, and brain areas associated with motor control and avoidance reactions to pain, such as the left cerebellum, when liked music was played in the background in comparison to disliked music. Importantly, the relationship between music listening and differences in pain ratings of two music conditions was mediated by the magnitude of right PreCG/PoCG and left cerebellum activations. These findings deepened our understanding of the analgesic benefits of background liked music, a property relevant to clinical applications.

EEG Beta functional connectivity decrease in the left amygdala correlates with the affective pain in fibromyalgia: A pilot study.

Fibromyalgia (FM) is a major chronic pain disease with prominent affective disturbances, and pain-associated changes in neurotransmitters activity and in brain connectivity. However, correlates of affective pain dimension lack. The primary goal of this correlational cross-sectional case-control pilot study was to find electrophysiological correlates of the affective pain component in FM. We examined the resting-state EEG spectral power and imaginary coherence in the beta (β) band (supposedly indexing the GABAergic neurotransmission) in 16 female patients with FM and 11 age-adjusted female controls. FM patients displayed lower functional connectivity in the High β (Hβ, 20-30 Hz) sub-band than controls (p = 0.039) in the left basolateral complex of the amygdala (p = 0.039) within the left mesiotemporal area, in particular, in correlation with a higher affective pain component level (r = 0.50, p = 0.049). Patients showed higher Low β (Lβ, 13-20 Hz) relative power than controls in the left prefrontal cortex (p = 0.001), correlated with ongoing pain intensity (r = 0.54, p = 0.032). For the first time, GABA-related connectivity changes correlated with the affective pain component are shown in the amygdala, a region highly involved in the affective regulation of pain. The β power increase in the prefrontal cortex could be compensatory to pain-related GABAergic dysfunction.

Perceived social support partially mediates the association between childhood abuse and pain-related characteristics.

Higher perceived social support has been shown to buffer the impact of negative stressful events like childhood abuse on health outcomes. Yet, the role of perceived social support as a mediator of the association between childhood abuse and pain-related characteristics is not well understood. The present study explored this premise. Patients (n = 1,542) presenting to a tertiary-care, outpatient pain clinic completed a cross-sectional survey consisting of regularly collected clinical data and validated measures. Path analysis suggested that the impact of childhood abuse on sensory and affective pain-related characteristics was partially explained by perceived emotional support. Survivors of childhood abuse display a more complex clinical pain phenotype and this extends to more negative perceptions of social support. Our findings may reflect processes whereby childhood abuse negatively impacts social relationships across the lifespan, and these negative social perceptions and relationships influence sensory and affective components of pain.

Lesions to both somatic and affective pain pathways lead to decreased salience network connectivity.

Human pain is a salient stimulus composed of two main components: a sensory/somatic component, carrying peripheral nociceptive sensation via the spinothalamic tract and brainstem nuclei to the thalamus and then to sensory cortical regions, and an affective (suffering) component, where information from central thalamic nuclei is carried to the anterior insula, dorsal anterior cingulate cortex and other regions. While the sensory component processes information about stimulus location and intensity, the affective component processes information regarding pain-related expectations, motivation to reduce pain and pain unpleasantness. Unlike investigations of acute pain that are based on the introduction of real-time stimulus during brain recordings, chronic pain investigations are usually based on longitudinal and case-control studies, which are limited in their ability to infer the functional network topology of chronic pain. In the current study, we utilized the unique opportunity to target the CNS's pain pathways in two different hierarchical locations to establish causality between pain relief and specific connectivity changes seen within the salience and sensorimotor networks. We examined how lesions to the affective and somatic pain pathways affect resting-state network topology in cancer patients suffering from severe intractable pain. Two procedures have been employed: percutaneous cervical cordotomy (n = 15), hypothesized to disrupt the transmission of the sensory component of pain along the spinothalamic tract, or stereotactic cingulotomy (n = 7), which refers to bilateral intracranial ablation of an area in the dorsal anterior cingulate cortex and is known to ameliorate the affective component of pain. Both procedures led to immediate significant alleviation of experienced pain and decreased functional connectivity within the salience network. However, only the sensory procedure (cordotomy) led to decreased connectivity within the sensorimotor network. Thus, our results support the existence of two converging systems relaying experienced pain, showing that pain-related suffering can be either directly influenced by interfering with the affective pathway or indirectly influenced by interfering with the ascending spinothalamic tract.

Nociception-Induced Changes in Electroencephalographic Activity and FOS Protein Expression in Piglets Undergoing Castration under Isoflurane Anaesthesia.

Simple SummaryEfficient analgesia during surgical piglet castration is an important animal welfare issue. The present study is part of a larger study designed to investigate the efficacy of four local anaesthetics (bupivacaine, lidocaine, mepivacaine and procaine) for analgesia during castration. In conscious piglets, it is difficult to distinguish between stress, e.g., due to handling, and pain during castration. Therefore, this study was conducted under light isoflurane anaesthesia. The level of anaesthesia was adjusted such that movement reactions to a peripheral nociceptive stimulus still occurred. We present the results of the investigation of two possible parameters for the detection of nociception: the reaction pattern in the electroencephalogram (EEG) and FOS protein expression in the spinal dorsal horn. In the electroencephalogram, a biphasic reaction pattern in response to noxious stimulation was detected that was attenuated or altered by the application of local anaesthetics. FOS expression, which was examined postmortem, was decreased after the administration of local anaesthetics, except for bupivacaine. Based on these results, local anaesthesia decreases nociceptive transmission during piglet castration in this experimental setup. When combined with the corresponding haemodynamic parameters and the evaluation of defensive movements presented elsewhere, an overall understanding of the nociceptive response to castration can be generated.The objective of this study was to investigate the electroencephalographic reaction pattern and FOS protein expression in male piglets undergoing surgical castration under light isoflurane anaesthesia with or without local anaesthesia. The experiment was conducted under isoflurane anaesthesia to exclude the effect of the affective components of pain on the measurements. Changes in the oscillatory activity of the cerebral cortex over a 90 s period after noxious stimulation or simulated interventions were analysed. FOS expression was determined postmortem by performing immunohistochemistry in the dorsal horn of the spinal cord. The analysis of the response to an interdigital pinch revealed a biphasic reaction pattern in the electroencephalogram (EEG) that similarly was observed for the surgical stimuli during the castration procedure in the group without analgesia. This EEG response was attenuated or altered by the application of local anaesthetics. Immunohistochemical staining for FOS indicated a lower expression in the handling and in three local anaesthetic groups than in the animals castrated without pain relief. The findings indicate that EEG and FOS expression may serve as indicators for nociception in piglets under light isoflurane anaesthesia. A lower activation of nociceptive pathways occurs during castration after the application of local anaesthetics. However, EEG and FOS analyses should be combined with additional parameters to assess nociception, e.g., haemodynamic monitoring.

Treatments perceived to be helpful for neuropathic pain after traumatic spinal cord injury: A multicenter cross-sectional survey study

Design Cross-sectional survey. Objective To evaluate the perceived helpfulness of pharmacological and non-pharmacological interventions and their combinations for neuropathic pain (NeuP) and subcategories of NeuP after spinal cord injury (SCI). Setting Six Spinal Cord Injury Model System Centers. Methods Three hundred ninety one individuals at least one year post traumatic SCI were enrolled. A telephone survey was conducted to determine the pharmacologic and non-pharmacologic treatments used in the last 12 months for each participant’s three worst pains, whether these treatments were “helpful”, and if currently used, each treatments’ effectiveness. Results Two hundred twenty participants (56%) reported 354 distinct NeuPs. Pharmacological treatments rated helpful for NeuP were non-tramadol opioids (opioids were helpful for 86% of opioid treated NeuPs), cannabinoids (83%), and anti-epileptics (79%). Non-pharmacological treatments rated helpful for NeuP were massage (76%), body position adjustment (74%), and relaxation therapy (70%). Those who used both opioids and exercise reported greater NeuP treatment helpfulness compared to participants using opioids without exercise (P = 0.03). Conclusions Opioids, cannabinoids, and massage were reported more commonly as helpful than treatments recommended as first-line therapies by current clinical practice guidelines (CPGs) for NeuP after SCI (antiepileptics and antidepressants). Individuals with SCI likely value the modulating effects of pharmacological and non-pharmacological treatments on the affective components of pain in addition to the sensory components of pain when appraising treatment helpfulness.

Distinct and sex-specific expression of mu opioid receptors in anterior cingulate and somatosensory S1 cortical areas.

The anterior cingulate cortex (ACC) processes the affective component of pain, whereas the primary somatosensory cortex (S1) is involved in its sensory-discriminative component. Injection of morphine in the ACC has been reported to be analgesic, and endogenous opioids in this area are required for pain relief. Mu opioid receptors (MORs) are expressed in both ACC and S1; however, the identity of MOR-expressing cortical neurons remains unknown. Using the Oprm1-mCherry mouse line, we performed selective patch clamp recordings of MOR+ neurons, as well as immunohistochemistry with validated neuronal markers, to determine the identity and laminar distribution of MOR+ neurons in ACC and S1. We found that the electrophysiological signatures of MOR+ neurons differ significantly between these 2 areas, with interneuron-like firing patterns more frequent in ACC. While MOR+ somatostatin interneurons are more prominent in ACC, MOR+ excitatory neurons and MOR+ parvalbumin interneurons are more prominent in S1. Our results suggest a differential contribution of MOR-mediated modulation to ACC and S1 outputs. We also found that females had a greater density of MOR+ neurons compared with males in both areas. In summary, we conclude that MOR-dependent opioidergic signaling in the cortex displays sexual dimorphisms and likely evolved to meet the distinct function of pain-processing circuits in limbic and sensory cortical areas.

ID:16361 Burst Stimulation Therapy Improves Pain Relief and Emotional Well-Being in Patients With Waning SCS Therapy

Spinal cord stimulation (SCS) is a safe and effective treatment option for patients with chronic intractable pain. However, a portion of patients with SCS eventually develop loss of efficacy for several reasons including habituation, lead migration, and new pain emergence. Burst stimulation offers a unique mechanism of action that can potentially restore effectiveness where other stimulation therapies have failed. While tonic SCS modulates the lateral pain pathway, only passive recharge burst1 has been shown to influence both the lateral and medial pain pathway responsible for affective components of pain, such as catastrophizing and depression in addition to sensory pain.

Distinct basolateral amygdala excitatory inputs mediate the somatosensory and aversive-affective components of pain

Pain is a multidimensional perception that includes unpleasant somatosensory and affective experiences; however, the underlying neural circuits that mediate different components of pain remain elusive. Although hyperactivity of basolateral amygdala glutamatergic (BLAGlu) neurons is required for the somatosensory and emotional processing of pain, the precise excitatory inputs to BLAGlu neurons and their roles in mediating different aspects of pain are unclear. Here, we identified two discrete glutamatergic neuronal circuits in male mice: a projection from the insular cortex glutamatergic (ICGlu) to BLAGlu neurons, which modulates both the somatosensory and affective components of pain, and a projection from the mediodorsal thalamic nucleus (MDGlu) to BLAGlu neurons, which modulates only the aversive-affective component of pain. Using whole-cell recording and fiber photometry, we found that neurons within the IC→BLA and MD→BLA pathways were activated in mice upon inflammatory pain induced by injection of complete Freund’s adjuvant (CFA) into their paws. Optical inhibition of the ICGlu→BLA pathway increased the nociceptive threshold and induced behavioral place preference in CFA mice. In contrast, optical inhibition of the MDGlu→BLA pathway did not affect the nociceptive threshold but still induced place preference in CFA mice. In normal mice, optical activation of the ICGlu→BLA pathway decreased the nociceptive threshold and induced place aversion, while optical activation of the MDGlu→BLA pathway only evoked aversion. Taken together, our results demonstrate that discrete ICGlu→BLA and MDGlu→BLA pathways are involved in modulating different components of pain, provide insights into its circuit basis, and better our understanding of pain perception.

The Affective Dimension of Pain Appears to Be Determinant within a Pain-Insomnia-Anxiety Pathological Loop in Fibromyalgia: A Case-Control Study.

Background: Fibromyalgia (FM) is a chronic pain disease characterized by multiple symptoms whose interactions and implications in the disease pathology are still unclear. This study aimed at investigating how pain, sleep, and mood disorders influence each other in FM, while discriminating between the sensory and affective pain dimensions. Methods: Sixteen female FM patients were evaluated regarding their pain, while they underwent—along with 11 healthy sex- and age-adjusted controls—assessment of mood and sleep disorders. Analysis of variance and correlations were performed in order to assess group differences and investigate the interactions between pain, mood, and sleep descriptors. Results: FM patients reported the typical widespread pain, with similar sensory and affective inputs. Contrary to controls, they displayed moderate anxiety, depression, and insomnia. Affective pain (but neither the sensory pain nor pain intensity) was the only pain indicator that tendentially correlated with anxiety and insomnia, which were mutually associated. An affective pain–insomnia–anxiety loop was thus completed. High ongoing pain strengthened this vicious circle, to which it included depression and sensory pain. Conclusions: Discriminating between the sensory and affective pain components in FM patients disclosed a pathological loop, with a key role of affective pain; high ongoing pain acted as an amplifier of symptoms interaction. This unraveled the interplay between three of most cardinal FM symptoms; these results contribute to better understand FM determinants and pathology and could help in orienting therapeutic strategies.

Altered prefrontal-striatal theta-band oscillatory dynamics underlie working memory deficits in neuropathic pain rats.

Prelimbic medial prefrontal cortex (PL-mPFC) and nucleus accumbens core region (NAcc) play an important role in supporting several executive cognitive mechanisms, such as spatial working memory (WM). Recently, this circuit has been also associated with both sensory and affective components of pain. However, it is still unclear whether this circuit is endogenously engaged in neuropathic pain-related cognitive dysfunctions. To answer this question, we induced the expression of halorhodopsin in local PL-mPFC neurons projecting to NAcc, and then selectively inhibited the terminals of these neurons in the NAcc while recording neural activity during the performance of a delayed non-match to sample (DNMS) spatial WM task. Within-subject behavioural performance and PL-mPFC to NAcc circuit neural activity was assessed after the onset of a persistent rodent neuropathic pain model-spared nerve injury (SNI). Our results revealed that the induction of the neuropathy reduced WM performance, and altered the interplay between PL-mPFC and NAcc neurons namely in increasing the functional connectivity from NAcc to PL-mPFC, particularly in the theta-band spontaneous oscillations; in addition, these behavioural and functional perturbations were partially reversed by selective optogenetic inhibition of PL-mPFC neuron terminals into the NAcc during the DNMS task delay-period, without significant antinociceptive effects. Altogether, these results strongly suggest that the PL-mPFC excitatory output into the NAcc plays an important role in the deregulation of WM under pain conditions. Selective optogenetic inhibition of prefrontal-striatal microcircuit reverses pain-related working memory deficits but has no significant impact on pain responses. Neuropathic pain underlies an increase of functional connectivity between the nucleus accumbens core area and the prelimbic medial prefrontal cortex mediated by theta-band activity.

The Role of Mediodorsal Thalamic Projections to Prelimbic Medial Prefrontal Cortex in Affective Pain Processing and Pain Tolerance

Both human and rodent studies demonstrate that the mediodorsal (MD) thalamus, a target of spinothalamic tract neurons, is involved in processing the affective component of pain. The specific role of MD nuclei and their projections in pain remains incompletely understood. MD projects to several cortical regions, one of which is the prelimbic region of the prefrontal cortex (PL), an area thought to play a role in pain processing and modulation. The purpose of this study was to elucidate the role of MD neurons that project to the PL in affective pain processing and pain tolerance. We utilized viral vectors and the Cre-lox system to specifically express designer receptors exclusively activated by designer drugs (DREADDs) in MD pyramidal neurons that project to the PL to activate or deactivate the circuit with CNO. Mice received chronic constriction injuries (CCI) contralateral to viral injections. This was followed by conditioned place aversion (CPA) or preference tests and the operant plantar thermal assay (OPTA). Activating the unilateral MD-PL circuit using excitatory DREADDs in naïve mice did not produce a conditioned place aversion. It did, however, produce place aversion in mice with CCI. Unilaterally inhibiting the MD-PL circuit in mice with CCI did not produce a place preference. There was no difference in the time spent tolerating a noxious temperature to receive a sucrose reward when this circuit was either activated or inhibited in mice with CCI. The MD-PL circuit is involved in the enhancement of aversion in mice with chronic pain. This circuit, however, is not sufficient to produce aversion in pain-free mice. This circuit may not be necessary for the affective component of pain, as unilaterally inhibiting it did not result in preference in mice with CCI. Finally, this circuit may not be involved with the modulation of pain tolerance in mice with CCI. Grant support from R01 NS107356.

Zona Incerta Modulates Pain-Associated Behaviors in Mice

Pain is an unpleasant experience with both sensory and affective components. However, the neural circuits underlying modulation of pain-related behaviors remains unclear. In this study, we identified an inhibitory neural circuit that originates in central amygdala protein kinase C-delta (CeA-PKCδ) neurons and terminates in the ventral sector of the zona incerta (ZI), a subthalamic structure previously linked to pain processing. Behavioral experiments show that chemogenetic inhibition of GABAergic ZI neurons induces bilateral hypersensitivity in uninjured mice as well as contralateral hypersensitivity after nerve injury. In contrast, chemogenetic activation of VGAT cells in the ZI reverses nerve injury-induced hypersensitivity. Furthermore, we found that chemogenetic activation of ZI-VGAT neurons reduced pain-related aversion during formalin conditioned place aversion (FCPA) without affecting spontaneous nociceptive responses induced by formalin. Taken together, our results suggest an indispensable role of ZI in regulating somatosensory and affective components of pain. Grant support from NCCIH.

Sensory Versus Affective Pain Descriptors Predicting Functional Versus Psychosocial Disability

In the lexical assessment of pain, an offshoot of the McGill Pain Questionnaire is the Pain Descriptor System (PDS) which assesses sensory, affective, and overall intensity of pain. To determine if sensory versus affective pain components might be selectively related to different aspects of disability, PDS scores were examined in relation to functional status and psychosocial impairment on the Pain Disability Questionnaire (PDQ). A sample of 629 chronic pain patients rated the degree to which each of 36 PDS words described their pain and also rated 15 items of the PDQ. Three regression models (including Group Lasso) were applied to the data. Results showed that as hypothesized, PDS sensory scores significantly predicted PDQ functional status, accounting for about 13% of the variance; PDS affective scores significantly predicted PDQ psychosocial impairment, accounting for 17% of the variance; PDS total scores significantly predicted PDQ total scores, accounting for approximately 24% of the variance. This supports the overall predictive validity of pain descriptors, while confirming more specific links between components of pain and facets of disability. Clinically, the patient's description of pain sensation may hold valuable clues to physical impairment, whereas the communication of affect/suffering is more likely to connote psychosocial difficulties in functioning. PerspectiveRegression models (including Group Lasso) were applied to data on pain and disability from 629 patients. Findings support the Pain Descriptor System in assessing pain but further suggest that sensory descriptors are predictive of physical impairment from chronic pain, whereas affective descriptors are more predictive of psychologically-related disability.

Unpleasant olfactory and gustatory stimuli increase pain unpleasantness in patients with chronic oral burning pain: An exploratory study.

BackgroundDespite mounting evidence for the powerful influence of smell and taste substances in experimental pain, our knowledge of their effects in the clinical context is scarce, especially for patients with chronic oral burning pain. To fill this gap, we investigated the effect of olfactory and gustatory stimuli on pain perception in patients with chronic oral burning pain, a disabling condition that is difficult to manage and treat.MethodsTwenty‐two patients with chronic oral burning pain underwent testing with a variety of olfactory and gustatory substances (pleasant, neutral, unpleasant) in multisensory interaction. The order of testing was randomized. Perception of pain intensity and unpleasantness was evaluated on a numerical rating scale at baseline and immediately after each test trial.ResultsPain unpleasantness but not pain intensity was found to be modulated by chemosensory stimuli. Unpleasant olfactory and gustatory stimuli increased the perception of pain unpleasantness compared to pleasant and neutral stimuli. Pain unpleasantness after unpleasant olfactory and gustatory stimuli correlated with psychological questionnaire subscale scores for distress (CORE‐OM) and emotional awareness (TAS‐20).ConclusionsOur findings suggest a role of unpleasant chemosensory stimuli in increasing the perception of pain unpleasantness in patients with chronic oral burning. The lack of an effect on pain intensity indicates a dissociation between sensory and affective pain components. Future research is needed to further study the association between chemosensory stimuli and emotional and subjective aspects in modulating chronic oral burning pain.SignificanceThis exploratory work suggests that unpleasant smell and taste stimuli may have an adverse effect on the affective component of chronic oral burning pain. Future comprehensive large‐scale research, also applying brain imaging investigations as well as full psychological analysis, is required to better understand the role of smell and taste stimuli on this chronic and disabling pain condition.