Increased Pain Sensitivity Research Articles

High-Fat Diet-Induced Blood-Brain Barrier Dysfunction: Impact on Allodynia and Motor Coordination in Rats.

The associations among increased pain sensitivity, obesity, and systemic inflammation have not been described as related to BBB dysfunctions. To analyze the metabolic, behavioral, and inflammatory effects of a high-fat diet (HFD) and ultrastructural modifications in brain regions, we used an in vivo experimental model. Adult male Wistar rats were randomly assigned to one of two conditions, an ad libitum control group or an HFD (60%)-fed group, for eight weeks. At the end of the protocol, glucose and insulin tolerance tests were performed. Additionally, we analyzed the response to a normally innocuous mechanical stimulus and changes in motor coordination. At the end of the protocol, HFD-fed rats presented increased HOMA-IR and metabolic syndrome (MetS) prevalence. HFD-fed rats also developed an increased nociceptive response to mechanical stimuli and neurological injury, resulting in impaired motor function. Hypothalamus and cerebellum neurons from HFD-fed rats presented with nuclear swelling, an absence of nucleoli, and karyolysis. These results reveal that HFD consumption affects vital brain structures such as the cerebellum, hippocampus, and hypothalamus. This, in turn, could be producing neuronal damage, impairing cellular communication, and consequently altering motricity and pain sensitivity. Although direct evidence of a causal link between BBB dysfunction and sensory-motor changes was not observed, understanding the association uncovered in this study could lead to targeted therapeutic strategies.

Investigating the effects of artificial baroreflex stimulation on pain perception: A comparative study in no-pain and chronic low back pain individuals.

The autonomic nervous system (ANS) and pain exhibit a reciprocal relationship, where acute pain triggers ANS responses, whereas resting ANS activity can influence pain perception. Nociceptive signalling can also be altered by 'top-down' processes occurring in the brain, brainstem and spinal cord, known as 'descending modulation'. By employing the conditioned pain modulation (CPM) paradigm, we previously revealed a connection between reduced low-frequency heart rate variability and CPM. Individuals with chronic pain often experience both ANS dysregulation and impaired CPM. Baroreceptors, which contribute to blood pressure and heart rate variability regulation, may play a significant role in this relationship, although their involvement in pain perception and their functioning in chronic pain have not been sufficiently explored. In the present study, we combined artificial 'baroreceptor stimulation' in both pressure pain and CPM paradigms, seeking to explore the role of baroreceptors in pain perception and descending modulation. In total, 22 individuals with chronic low back pain (CLBP) and 29 individuals with no-pain (NP) took part in the present study. We identified a differential modulation of baroreceptor stimulation on pressure pain between the groups of NP and CLBP participants. Specifically, NP participants perceived less pain in response to baroreflex activation, whereas CLBP participants exhibited increased pain sensitivity. CPM scores were associated with baseline measures of baroreflex sensitivity in both CLBP and NP participants. Our data support the importance of the baroreflex in chronic pain and a possible mechanism of dysregulation involving the interaction between the ANS and descending pain modulation. KEY POINTS: Baroreflex stimulation has different effects on pressure pain in participants with chronic pain compared to matched individuals with no-pain. Baroreceptor activation decreases pain in participants with no-pain but increases pain perception in participants with chronic pain. Baroreflex sensitivity is associated with conditioned pain modulation in both groups of chronic pain and no-pain participants. The reactivity of the baroreflex during autonomic stress demonstrated a positive correlation with Pain Trait scores in participants with chronic back pain.

Cannabigerol Reduces Acute and Chronic Hypernociception in Animals Exposed to Prenatal Hypoxia-Ischemia

Cannabigerol (CBG), a phytocannabinoid, has shown promise in pain management. Previous studies by our research group identified an increase in pain sensitivity as a consequence of prenatal hypoxia-ischemia (HI) in an animal model. This study aimed to investigate the efficacy of CBG in acute and chronic hyperalgesia induced by prenatal HI. A pharmacological screening was first conducted using hot plate and open-field tests to evaluate the antinociceptive and locomotor activities of animals administered with a 50 mg/kg oral dose of cannabis extract with a high CBG content. Prenatal HI was induced in pregnant rats, and the offspring were used to evaluate the acute antinociceptive effect of CBG in the formalin-induced peripheral pain model, while chronic antinociceptive effects were observed through spinal nerve ligation (SNL) surgery, a model used to induce neuropathic pain. Our results show that CBG exhibited an antinociceptive effect in the hot plate test without affecting the animals’ motor function in the open-field test. CBG significantly reduced formalin-induced reactivity in HI offspring during both the neurogenic and inflammatory phases. CBG treatment alleviated thermal and mechanical hypernociception induced by SNL. Biomolecular analysis revealed CBG’s ability to modulate expression, particularly reducing TNFα and Nav1.7 in HI male and female rats, respectively. These results highlight CBG as a potential antinociceptive agent in acute and chronic pain models, suggesting it as a promising therapeutic option without inducing motor impairment. Further research is needed to fully elucidate its mechanisms and clinical applications in pain management.

Qualitative Research on the Causes of Kinesiophobia in Postoperative Cerebellar Tumor Patients.

To understand the causes of kinesiophobia in postoperative patients with cerebellar tumors, and to provide the basis for early rehabilitation regimen. Using the objective sampling method, 16 postoperative cerebellar tumor patients were extracted for semi-structured interviews. Data was analyzed using the Colaizzi 7-step method, and the theme was refined. The causes of kinesiophobia in postoperative cerebellar tumor patients were summarized into 4 themes: Excessive vigilance to self-state. Increased pain sensitivity and fear of dizziness were regarded as threat signals, which brought excessive burden on the current therapeutic regimen. Uncertainty of early rehabilitation. Lack of cognition, uncertainty effect of early rehabilitation, and insufficient exercise of self-efficacy. Psychological stress and avoidant emotion. Economic pressure and avoidant emotion ran out of control. Vulnerable support system. Deficient in professional technique, family, and social support. The kinesiophobia in postoperative cerebellar tumor patients is composed of multiple factors. Medical staff are supposed to help patients establish a correct perception of disease status. The information on early rehabilitation needs to be transmitted continually. To promote patients to participate in early rehabilitation activities energetically, it is vital to keep a high level of rehabilitation effect expectation, increased self-exercise efficiency, psychological intervention, and strong multi-party cooperation in an improved social support system.

Diabetic Neuropathic Pain and Circadian Rhythm: A Future Direction Worthy of Study.

More than half of people with diabetes experience neuropathic pain. Previous research has shown that diabetes patients' neuropathic pain exhibits a circadian cycle, which is characterized by increased pain sensitivity at night. Additional clinical research has revealed that the standard opioid drugs are ineffective at relieving pain and do not change the circadian rhythm. This article describes diabetic neuropathic pain and circadian rhythms separately, with a comprehensive focus on circadian rhythms. It is hoped that this characteristic of diabetic neuropathic pain can be utilized in the future to obtain more effective treatments for it.

Hyperalgesia in Patients With a History of Opioid Use Disorder

Short-term and long-term opioid treatment have been associated with increased pain sensitivity (ie, opioid-induced hyperalgesia). Treatment of opioid use disorder (OUD) mainly involves maintenance with methadone and buprenorphine, and observations of heightened cold pain sensitivity among patients are often considered evidence of opioid-induced hyperalgesia. To critically examine the evidence that hyperalgesia in patients with OUD is related to opioid use. Web of Science, PubMed, and Embase between March 1, 2023, and April 12, 2024, were searched. Studies assessing cold pressor test (CPT) pain responses during treatment seeking, pharmacological treatment, or abstinence in patients with OUD history were included. Multilevel random-effects models with robust variance estimation were used for all analyses. Study quality was rated with the JBI checklist. Funnel plots and Egger regression tests were used to assess reporting bias. Main outcomes were pain threshold, tolerance, and intensity in patients and healthy controls, and unstandardized, standardized (Hedges g), and percentage differences (%Δ) in these measures between patients and controls. The association between pain sensitivity and opioid tolerance, withdrawal, and abstinence indices was tested with meta-regression. Thirty-nine studies (1385 patients, 741 controls) met the inclusion criteria. Most studies reported CPT data on patients undergoing opioid agonist treatment. These patients had a mean 2- to 3-seconds lower pain threshold (95% CI, -4 to -1; t test P = .01; %Δ, -22%; g = -0.5) and 29-seconds lower pain tolerance (95% CI, -39 to -18; t test P < .001; %Δ, -52%; g = -0.9) than controls. Egger tests suggested that these differences may be overestimated. There were some concerns of bias due to inadequate sample matching and participant dropout. Meta-regressions yielded no clear support for hyperalgesia being opioid related. Patients receiving opioid agonist treatment for OUD are hypersensitive to cold pain. It remains unclear whether hyperalgesia develops prior to, independent of, or as a result of long-term opioid treatment. Regardless, future studies should investigate the impact of hyperalgesia on patients' well-being and treatment outcomes.

Revealing a role of brainstem monoaminergic nuclei on the pronociceptive effect of sleep restriction

Sleep disturbances and persistent pain conditions are public health challenges worldwide. Although it is well-known that sleep deficit increases pain sensitivity, the underlying mechanisms remain elusive. We have recently demonstrated the involvement of nucleus accumbens (NAc) and anterior cingulate cortex (ACC) in the pronociceptive effect of sleep restriction. In this study, we found that sleep restriction increases c-Fos expression in NAc and ACC, suggesting hyperactivation of these regions during prolonged wakefulness in male Wistar rats. Blocking adenosine A2A receptors in the NAc or GABAA receptors in the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), or locus coeruleus (LC) effectively mitigated the pronociceptive effect of sleep restriction. In contrast, the blockade of GABAA receptors in each of these nuclei only transiently reduced carrageenan-induced hyperalgesia. Pharmacological activation of dopamine D2, serotonin 5-HT1A and noradrenaline alpha-2 receptors within the ACC also prevented the pronociceptive effect of sleep restriction. While pharmacological inhibition of these same monoaminergic receptors in the ACC restored the pronociceptive effect which had been prevented by the GABAergic disinhibition of the of the VTA, DRN or LC. Overall, these findings suggest that the pronociceptive effect of sleep restriction relies on increased adenosinergic activity on NAc, heightened GABAergic activity in VTA, DRN, and LC, and reduced inhibitory monoaminergic activity on ACC. These findings advance our understanding of the interplay between sleep and pain, shedding light on potential NAc-brainstem-ACC mechanisms that could mediate increased pain sensitivity under conditions of sleep impairment.

Chronic Administration of Cannabinoid Agonists ACEA, AM1241, and CP55,940 Induce Sex-Specific Differences in Tolerance and Sex Hormone Changes in a Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB1)-selective, cannabinoid receptor type 2 (CB2)-selective, and CB1/CB2 mixed agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. SIGNIFICANCE STATEMENT: CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

The effects of morphine administration on the central nervous system (CNS): advantages and disadvantages

Morphine, a potent opioid analgesic, plays a critical role in pain management but elicits complex effects on the central nervous system (CNS), demonstrating both beneficial and detrimental outcomes. This paper reviews preclinical studies to examine morphine's interactions with the CNS, notably via binding to opioid receptors, leading to analgesia as well as a series of adverse effects, including addiction, tolerance, and neurological impairments. Acute exposure to morphine alters neurotransmitter activity, gene expression, and neuronal firing rates. In contrast, chronic use results in significant neuronal damage, altered memory functions, increased pain sensitivity, and neuroinflammation, highlighting the drug's impact on neurogenesis and neural cell viability. Additionally, morphine's protective properties against neurotoxic insults are discussed, alongside its potential to disrupt cellular and molecular pathways, culminating in neurotoxicity and cognitive deficits. Given the dual nature of morphine's impact on the CNS - protective vs. harmful, depending on specific conditions such as dosage, disease type, and administration frequency - this paper underscores the necessity for further research to untangle this complex interplay to leverage morphine's pain management benefits while minimizing its risks. A thorough evaluation of morphine administration practices can help reconcile these conflicting results.

Substance P's Impact on Chronic Pain and Psychiatric Conditions-A Narrative Review.

Substance P (SP) plays a crucial role in pain modulation, with significant implications for major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Elevated SP levels are linked to heightened pain sensitivity and various psychiatric conditions, spurring interest in potential therapeutic interventions. In chronic pain, commonly associated with MDD and anxiety disorders, SP emerges as a key mediator in pain and emotional regulation. This review examines SP's impact on pain perception and its contributions to MDD, anxiety disorders, and PTSD. The association of SP with increased pain sensitivity and chronic pain conditions underscores its importance in pain modulation. Additionally, SP influences the pathophysiology of MDD, anxiety disorders, and PTSD, highlighting its potential as a therapeutic target. Understanding SP's diverse effects provides valuable insights into the mechanisms underlying these psychiatric disorders and their treatment. Further research is essential to explore SP modulation in psychiatric disorders and develop more effective treatment strategies.

The role of self-reported and physiological stress in nocebo hyperalgesia

Negative expectations can increase pain sensitivity, leading to nocebo hyperalgesia. However, the physiological and psychological factors that predispose individuals to this phenomenon are still not well understood. The present study examined whether stress induced by a social stressor affects nocebo hyperalgesia, and whether this effect is mediated by self-reported and physiological stress responses. We recruited 52 healthy participants (15 men) who were randomly assigned to either the Trier Social Stress Test (TSST) or a control condition (a friendly version of the TSST). Nocebo hyperalgesia was induced using negative suggestions combined with a validated pain conditioning paradigm. We assessed self-reported (anxiety and stress) and physiological (cortisol, alpha-amylase, heart rate, and skin conductance) responses to stress. Both groups exhibited significant nocebo hyperalgesia. The stress group showed higher levels of anxiety, self-reported stress, and cortisol levels compared to the control group while no significant differences were found in other physiological markers. The stress and control groups did not differ in the magnitude of nocebo hyperalgesia, but anxiety levels partially mediated the effects of the stress test on nocebo hyperalgesia. Our findings suggest that an external social stressor does not directly affect nocebo hyperalgesia, but that increased anxiety due to the stressor enhances its magnitude. Thus, it may be worthwhile to investigate whether reducing stress-related anxiety in clinical settings would help alleviate nocebo effects.

Associations between pain intensity, pain sensitivity, demographics, psychological factors, disability, physical activity, pain phenotype and COVID-19 history in low back pain: An observational study.

Knowledge of the factors affecting pain intensity and pain sensitivity can inform treatment targets and strategies aimed at personalizing the intervention, conceivably increasing its positive impact on patients. Therefore, this study aimed to investigate the association between demographic factors (sex and age), body mass index (BMI), psychological factors (anxiety and depression, kinesiophobia and catastrophizing), self-reported physical activity, pain phenotype (symptoms of central sensitization, and nociceptive or neuropathic pain), history of COVID-19 and pain intensity and sensitivity in patients with chronic non-specific low back pain (LBP). This was a cross-sectional secondary analysis with 83 participants with chronic non-specific LBP recruited from the community between August 2021 and April 2022. BMI, pain intensity (Visual Analog Scale), pain sensitivity at the lower back and at a distant point [pressure pain threshold], catastrophizing (Pain Catastrophizing Scale), kinesiophobia (Tampa Scale for Kinesiophobia), anxiety and depression (Hospital Anxiety and Depression Scale), pain phenotype (Central Sensitization Inventory and PainDetect Questionnaire), physical activity (International Physical Activity Questionnaire), and disability (Roland Morris Disability Questionnaire) were assessed. Multiple linear regression analyses with pain intensity and sensitivity as the dependent variables were used. The model for pain intensity explained 34% of its variance (Adjusted R2=-0.343, p<0.001), with depression and anxiety (p=0.008) and disability (p=0.035) reaching statistical significance. The model for pain sensitivity at the lower back, also explained 34% of its variance (Adjusted R2=0.344, p<0.001) at the lower back with sex, BMI, and kinesiophobia reaching statistical significance (p<0.05) and 15% of the variance at a distant body site (Adjusted R2=0.148, p=0.018) with sex and BMI reaching statistical significance (p<0.05). This study found that different factors are associated with pain intensity and pain sensitivity in individuals with LBP. Increased pain intensity was associated with higher levels of anxiety and depression and disability and increased pain sensitivity was associated with being a female, higher kinesiophobia, and lower BMI.

Depression and Time to Knee Arthroplasty Among Adults Who Have Knee Osteoarthritis

BackgroundDepression is common in osteoarthritis (OA) and is associated with poor outcomes following total knee arthroplasty (TKA). Depression can increase pain sensitivity and may be related to an increased likelihood of TKA. MethodsNationally distributed electronic health record data from 2010 to 2018 were used to identify eligible patients (n = 9,466) who had knee OA and were 45 to 80 years of age. Cox proportional hazard models were computed to estimate the association between depression and incident TKA for all patients and by age group (45 to 54, 55 to 64, and 65 to 80 years of age). Confounding was controlled using entropy balancing. Sensitivity analyses determined if the association between depression and TKA differed when depression occurred in the 12 months occurring 90, 60, 30, and 0 days lag time before TKA. ResultsThe mean age of the sample was 63 (range, 45 to 80), 64.0% were women, 83.3% were White race, and approximately 50% resided in the Midwest. There was no association between depression and incident TKA (hazard ratio = 0.97; confidence interval = 0.81 to 1.16]). Results did not differ in age-stratified analyses. Sensitivity analyses revealed a higher percentage of TKA among depressed versus nondepressed patients (24.2 versus 21.6%; P = .028) when the patient’s depression diagnosis was established in the 12 months with no lag time before TKA. ConclusionsPatients who have knee OA and comorbid depression, compared to those who have only knee OA, do not have an increased likelihood of TKA. The multifactorial, complex decision to obtain TKA does not appear to be influenced by depression, but depression is a common comorbidity.

The relationship between traumatic exposure and pain perception in children: the moderating role of posttraumatic symptoms.

Adverse childhood experiences (ACEs) affect approximately half of all children worldwide. These experiences have been linked to increased pain sensitivity in adulthood and a higher likelihood of developing severe chronic pain. However, most studies have assessed the effects of ACEs retrospectively, long after they occurred, leaving room for other factors to influence the observed outcomes. We investigated, for the first time, the association between ACEs and concurrent pain perception among young children who live in a conflict zone and are consistently exposed to potentially traumatic experiences. Participants were 60 elementary school children (ages 8-11 years) living in conflict regions (n = 39) or nonconflict regions (n = 21). Posttraumatic stress symptom (PTSS) severity, traumatic exposure, pressure pain threshold (PPT), and mechanical detection threshold (MDT) were measured. Trauma-exposed children had significantly lower PPT than did controls, but MDT was similar across groups. Pressure pain threshold correlated positively with proximity to the conflict zone and inversely with traumatic exposure magnitude and PTSS severity. In addition, PTSSs moderated the relationship between repeated traumatic exposure and PPT. Children with higher PTSS severity displayed pain hypersensitivity regardless of their traumatic exposure level, whereas in children with lower PTSS severity, greater traumatic exposure correlated with pain hypersensitivity. The results suggest that ACEs among children lead to concurrent pain hypersensitivity and distress and may put them at elevated risk of chronic pain early in life. In addition, our findings emphasize the need for identifying children with various PTSS levels to provide tailored interventions and mitigate the long-term negative effects of ACEs.

A Narrative Review of the Reciprocal Relationship Between Sleep Deprivation and Chronic Pain: The Role of Oxidative Stress.

Sleep is crucial for human health, insufficient sleep or poor sleep quality may negatively affect sleep function and lead to a state of sleep deprivation. Sleep deprivation can result in various health problems, including chronic pain. The intricate relationship between sleep and pain is complex and intertwined, with daytime pain affecting sleep quality and poor sleep increasing pain intensity. The article first describes the influence of sleep on the onset and development of pain, and then explores the impact of daytime pain intensity on nighttime sleep quality and subsequent pain thresholds. However, the primary emphasis is placed on the pivotal role of oxidative stress in this bidirectional relationship. Although the exact mechanisms underlying sleep and chronic pain are unclear, this review focuses on the role of oxidative stress. Numerous studies on sleep deprivation have demonstrated that it can lead to varying degrees of increased pain sensitivity, while chronic pain leads to sleep deprivation and further exacerbates pain. Further research on the role of oxidative stress in the mechanism of sleep deprivation-induced pain sensitization seems reasonable. This article comprehensively reviews the current research on the interrelationship between sleep deprivation, pain and the crucial role of oxidative stress.

Dissecting the interaction of pain and respiration at the level of the rostral ventromedial medulla via cell-type specific manipulations

Opioid drugs are highly effective for pain management, but they also cause respiratory depression. This life-threatening side-effect of opioid use occurs due to the interacting and/or overlapping neuronal circuits that regulate pain and breathing. Understanding the brain regions and cell-types that link pain and breathing will be essential to develop safer pain management strategies. Opioid analgesia involves altered firing patterns of neurons within the rostral ventromedial medulla (RVM). Although the RVM is known for its role in descending pain modulation, local administration of opioids within the RVM induces potent respiratory depression in addition to analgesia. The RVM has two main classes of neurons identified based on their firing response to pain stimuli. As their name suggests, “ON-cells” are activated during pain and “OFF-cells” are inhibited. Pharmacological and electrophysiological studies have shown that ON-cells express the μ-opioid receptor (MOR) and respond directly to opioids. Moreover, it is thought that the activity of ON-cells facilitates pain and respiration, and that opioid suppression of ON-cells contributes to respiratory depression. In contrast, OFF-cells do not appear to express MOR; however, activation of these neurons is required for opioid-induced analgesia. Therefore, changes in OFF-cells activity may more selectively affect pain thresholds. Due to a lack of selective pharmacological agents, directly testing these predictions has not been possible. Moreover, ON-cells can be excitatory or inhibitory, whereas OFF-cells are mostly inhibitory, adding another layer of complexity to their proposed functions. Here, we dissect these RVM subpopulations using modern intersectional genetic approaches to selectively manipulate RVM neurons based on expression of Oprm1 (the gene encoding MOR), as well as genetic markers for excitatory (Vglut2) or inhibitory (Vgat) neurotransmitter phenotypes. To examine the functional effects of Oprm1+ RVM neurons, an AAV designed to express Cre-dependent ChR2 was injected into the RVM of Oprm1Cre mice, followed by the implantation of an optical fiber. Respiratory activity of awake mice was then recorded using plethysmography during optogenetic stimulation of Oprm1+ RVM neurons. Consistent with the expected effects of ON-cells, breathing rate was increased to 5-6 Hz for the duration of the stimulation, and mice exhibited flinching and freezing behavior at light onset. In a second set of experiments, double transgenic Oprm1Cre; Vglut2FlpO mice were injected with an AAV that expresses ChR2 only when FlpO is present but Cre is absent (i.e. FlpO NOT Cre). Using this strategy, we were able to selectively target excitatory RVM neurons that do not express MOR. Optogenetic stimulations of these neurons during plethysmography revealed no changes in breathing or notable behavioral responses. However, paw withdrawal thresholds tested using Hargreaves’ method suggest that optogenetic activation of these neurons increases pain sensitivity. Our ongoing work will expand on these preliminary findings by using this approach to specifically manipulate Oprm1+;Vglut2+, Oprm1+;Vgat+, and Oprm1-;Vgat+ neurons to assess the roles of these RVM subpopulations in the regulation of pain and breathing. (NAB) R00HL145004; R01HL166317 (RSP) K01DA058543. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

P101 Investigating the association between clinical enthesitis and central sensitisation in psoriatic arthritis

Abstract Background/Aims Psoriatic Arthritis (PsA) is an inflammatory arthritis with enthesitis as its characteristic clinical feature. Enthesitis can be clinically challenging to differentiate from the widespread pain associated with Fibromyalgia (FM), the prototype of central sensitisation (CS) present in up to 30% of PsA patients. Algometry is used in CS research to quantify pressure pain threshold (PPT), reflecting increased pain sensitivity when reduced. Ultrasound is a valuable tool to evidence entheseal inflammatory changes in PsA. This study investigates associations between CS, i.e., FM, and entheseal ultrasound outcomes to better characterise pain mechanisms in PsA enthesitis. Methods A total of 20 patients with active PsA about to start a new immunosuppressant were recruited. Ultrasound evaluation of non-dominant knee (left for all patients) using dynamic B-mode and power Doppler was performed alongside the Leeds Enthesitis Index (LEI) collection to assess enthesitis. PPT was measured with algometry at the non-dominant knee (enthesitis), trapezius and calf muscle (CS areas), and collection of the ACR 2011 FM criteria was used to determine the presence of CS. Non-dominant areas were selected because they are less likely to exhibit biomechanical ultrasound alterations; moreover, the non-dominant side is generally more sensitive than the dominant side, thus enabling more precise PPT measurements. Correlations and t-tests were used to test associations between variables collected. SPSS was used to analyse the data. Results The 30% of patients met the FM criteria and presented higher LEI scores and lower PPT evoked threshold than FM-negative patients. Total FM scores significantly correlated with LEI scores (r = 0.69, p &amp;lt; 0.001) and calf PPTs (r=-0.53, p=-0.014), but not with knee and trapezius PPTs (r=-0.49, p = 0.09; r=-0.30, p = 0.19), or US enthesitis (r=-0.04, p = 0.86). PPTs in the areas investigated did not show significant correlations with US enthesitis, while an indirect association was observed between LEI with calf PPT (r=-0.51, p = 0.02) and trapezius PPT (r=-0.41, p = 0.06). No significant correlation was demonstrated between LEI and left knee enthesitis (r=-0.32, p = 0.17). Conclusion FM is frequent in PsA and can mimic entheseal pain, as suggested by the strong correlation with the LEI scores. In our cohort, LEI scores did not efficiently capture inflammatory enthesitis, demonstrated by the lack of association with ultrasound data. Moreover, the association between objective measurement of CS, including calf and trapezius PPTs, supports that LEI score may primarily reflect the presence of central sensitisation rather than inflammation. Therefore, relying solely on clinical detection of enthesitis may result in inappropriate treatment escalation. Ultrasound, conversely, serves as a dependable tool for confirming enthesitis and providing valuable information for making informed treatment decisions. Disclosure N.M. Aldehmi: None. N. Basu: None. J. Dale: None. A. Najm: None. F. Sunzini: None.

Structural alterations and pain perception at the ankle joint in patients with haemophilia.

Patients with haemophilia (PwH) suffer from chronic pain due to joint alterations induced by recurring haemorrhage. This study aimed to investigate the relationship between structural alterations and pain perception at the ankle joint in PwH. Ankle joints of 79 PwH and 57 healthy controls (Con) underwent ultrasound examination (US) and assessment of pain sensitivity via pressure pain thresholds (PPT). US discriminated between joint activity (synovitis) and joint damage (cartilage and/or bone degeneration) applying the HEAD-US protocol. Based on US-findings, five subgroups were built: PwH with activity/damage, PwH with activity/no damage, PwH with no activity/no damage, controls with activity/no damage and controls with no activity/no damage. Joint activity and joint damage were significantly increased in ankles of PwH compared to Con (p ≤.001). Subgroup analysis revealed that structural alterations negatively impact pain perception. This is particularly evident when comparing PwH with both activity/damage to PwH with no activity/no damage at the tibiotalar joint (p=.001). At the fibulotalar joint, no significant differences were observed between PwH subgroups. Further analysis showed that both joint activity and joint damage result in an increase in pain sensitivity (p ≤.001). The data suggest a relation between joint activity, joint damage and pain perception in PwH. Even minor changes due to synovitis appear to affect pain perception, with the effect not intensifying at higher levels of inflammation. In terms of joint damage, severe degeneration leads to a sensitised pain state most robustly, whereas initial changes do not seem to significantly affect pain perception.

Monosodium iodoacetate induces Cartilage degradation and inflammation in rats in a dose- and time-dependent manner

Monosodium iodoacetate (MIA) is a widely recognized agent for inducing cartilage degradation and inflammation in animal models. In this study, we systematically investigated the dose- and time-dependent effects of MIA on cartilage degradation in the knees of rats. We evaluated knee diameter, knee bend score, and the levels of pro-inflammatory cytokines (IL-1 and IL-8) and cartilage degradation markers (CTX-II) to gain insights into cartilage damage and inflammation progression. Wistar rats were categorized into groups receiving various doses of MIA via intra-articular injection (0.1 mg, 0.5 mg, 1 mg, 3 mg, and 5 mg) and were observed at multiple time intervals (2, 4, 6, 8, 10, and 12 weeks). We measured knee diameter to gauge joint swelling, assigned knee bend scores to assess functional limitations, and analyzed synovial fluid samples for IL-1β, IL-8, and CTX-II levels. Our data show that low-dose MIA increases pain sensitivity, knee diameter, inflammatory cytokines IL-1β and IL-8, and CTX-II levels, which progress slowly over 12 weeks. On the other hand, higher dosages of MIA caused cartilage deterioration after two weeks, followed by an increase in inflammatory cytokines. This research sheds light on MIA administration's dose- and time-dependent effects on cartilage breakdown and inflammation in rat knee joints. Analyzing knee diameter, knee bend score, IL-1β, IL-8, and CTX-II as evaluation parameters provides a multidimensional perspective of cartilage injury and inflammatory dynamics. These findings help us comprehend cartilage-related illnesses and have implications for future research on therapeutic approaches for cartilage disorders.

Correlation between the Degree of Psychological Stress with Pain Intensity in Tension-Type Headache Patients

Tension-Type Headache (TTH) is a critical health problem, particularly in Indonesia, with psychological stress being the most recognized contributing factor. The mechanism by which stress contributes to TTH is not fully understood, but stress has been found to increase pain sensitivity in peripheral or central patients with TTH, alongside the influence of biopsychosocial factors in different individuals. Therefore, this study aimed to analyze the relationship between the degree of psychological stress and pain intensity in patients with TTH at Dr. H. Moch Ansari Saleh Banjarmasin General Hospital. This observational analytic study was carried out using a cross-sectional approach and the 30 samples employed were taken through a systematic random sampling technique. The data was analyzed using Spearman's test. Our result showed that 63.33% of patients had mild stress, while 36.67% were moderate. In the mild stress group, there were 15.79% mild pain, 73.68% moderate pain, and 10.53% severe pain. Meanwhile, in the moderate stress group, 72.73% reported moderate pain, and 27.27% had severe pain. In conclusion, this study indicated there was a correlation between the degree of psychological stress and the intensity of pain in TTH patients, despite not statistically significant (p=0.102 and R=0.304).