Effects of Acetaminophen on Pain Response among Overweight or Obese Women Exposed to Weight Stigmatization

Landers, Jacob David The Ohio State University ProQuest Dissertations & 2021 해외박사(DDOD)

Pain is widely prevalent across the world, and individuals with excess weight are disproportionally affected by it relative to those with normal weight. Research suggests that obesity is associated with biological indicators of systemic inflammation (e.g., C-reactive protein), which may contribute to pain. Individuals with excess weight, especially women, also are at greater risk of experiencing the emotional pain of weight stigma, which may in turn exacerbate physical pain. Recent studies have shown that brain areas involved in the processing of physical pain (dorsal anterior cingulate cortex, anterior insula) are the same areas associated with emotional pain, and that analgesics (e.g., acetaminophen) used for reducing physical pain may also dampen extremity of emotional responses. However, analgesic effects have not been tested in the context of individuals with excess weight experiencing weight stigmatization.The current study was designed to 1) evaluate the influence of a weight stigma induction and acute dose of acetaminophen on pain, distress, and affect among women with overweight or obesity; and 2) evaluate the relationship between body mass index (BMI) and pain, the degree to which this relationship is mediated by weight stigma, and the degree to which acetaminophen moderate the weight stigma-pain relationship.One hundred sixty women with overweight or obesity (78% Caucasian; average age 41.7¡¾17.4 years; average BMI 32.4¡¾6.4) were recruited from the Columbus and surrounding communities. Prospective participants were screened for eligibility including BMI 25 or greater, female sex, and age 18 years or greater. The sample of eligible participants was stratified by age (18-40 years vs. over 40 years) and BMI (overweight vs. obese) for randomization into one of four study conditions: acetaminophen and weight stigma induction; placebo and weight stigma induction; acetaminophen and control condition; and placebo and control condition.Participants attended one, 120-minute session that began with anthropometric measurements, as well as collection of blood and saliva samples to measure inflammation. Participants were then administered either acetaminophen or placebo according to their randomization. Participants completed self-report questionnaires for sixty minutes while waiting for sufficient drug absorption, after which they were presented with the induction to which they were randomly assigned. Participants next completed a second set of self-report measures to assess the influence of the induction and they provided a second saliva sample to assess acute change in inflammation.Data analyses primarily included Pearson correlations; analyses of variance and covariance; and mediation and moderation analyses using PROCESS (Hayes, 2013). Results indicated that higher BMI was associated with greater endorsement of weight stigma, worse weight-related and physical quality of life, and greater pain. Higher baseline inflammation (C-reactive protein) was associated with higher BMI and greater perceived weight stigma. Group comparisons revealed more negative affect and distress among those exposed to weight stigmatization after ingesting acetaminophen compared to the two control condition groups. Post-hoc analyses revealed greater anxiety and distress in the acetaminophen and weight stigma group compared to the other three groups. Although weight stigma did not mediate the relationship of BMI to pain, post-hoc analyses indicated serial mediation of the BMI-pain relationship through both greater endorsement of weight stigma and greater distress. In contrast to study hypotheses, greater internalized weight stigma and greater BMI in the presence of acetaminophen was associated with greater post-induction pain.Results of the study conflict with prior published research suggesting a blunting effect of acetaminophen on emotional pain response but are consistent with newer, unpublished data demonstrating exacerbated emotional response with acetaminophen ingestion. These results support the relevance of physical and emotional pain for women with overweight or obesity, and suggest the need for further investigation into the effects of acetaminophen on emotional response among adults with overweight or obesity. Additionally, study results highlight the relevance of distress when considering the role of weight stigma in the BMI-pain relationship.

(The) effect of pain invalidation on depression of chronic pain patients : the mediating roles of social constraint and loneliness

이다예 Graduate School, Korea University 2022 국내석사

People with chronic pain feel the need to share their distress about pain with others, expecting to be understood and accepted. Unfortunately, many qualitative studies of chronic pain narratives have reported that chronic pain patients typically face other people’s reactions distrusting or belittling their pain experiences. Consequently, invalidation of pain by others can lead to a sense of social constraints that suppress disclosure. Despite the increased interest in pain communication, few studies have investigated quantitative associations of how pain invalidation affects patients’ psychological distress by changing their perceptions of whether the pain disclosure is acceptable within their social networks. Therefore, the present study aimed to examine whether pain invalidation increases patients’ depression through social constraints and loneliness. A total of 82 chronic pain patients were asked to write a narrative on how others responded when they expressed their distress about pain. Narratives were coded for pain invalidation using a coding scheme developed by the author. After that, participants rated self-reported measures including social constraint, loneliness, and depression. As hypothesized, the results indicated that there is a significant indirect effect of pain invalidation on depression through perceived social constraint and loneliness in a serial manner. Gender, age, and severity of pain were entered as covariates. Taken together, this study contributed to the idea that supportive social environments and pain communication are important to prevent the psychological maladjustment of chronic pain patients. Theoretical implications and future research directions are discussed. 만성통증 환자들은 자신의 낫지 않는 증상에 대한 고충을 이야기하고, 다른 사람들에게 이해받고 싶은 욕구가 있다. 그러나 선행 연구에 따르면, 만성통증 환자들은 종종 주변 사람들이 통증의 존재를 인정하지 않거나, 축소하는 것을 경험하며, 그로 인해 자신의 이야기를 마음껏 할 수 없는 사회적 제약을 느끼게 된다. 그러나 통증 불인정이 사회적 제약을 만들고, 그것이 외로움을 통해 우울이라는 심리적 부적응을 낳는 경로를 실증적으로 검증한 연구는 아직 없었다. 이에 본 연구는 타인의 통증에 대한 불인정 반응이 환자가 마음껏 통증에 대해 이야기하지 못하게 하는 사회적 제약으로 연결되며, 그 결과 외로움과 우울이 순차적으로 증가하는지 연쇄매개 모형을 살펴보았다. 국내 온라인 커뮤니티에서 만성통증 환자 83명을 모집하고, 불성실 응답자 1명을 제외한, 총 82명의 자료를 분석했다. 우선, 참여자들에게 자신의 통증 이야기에 대한 사회적 반응에 대한 경험을 서사로 작성하게 한 뒤, 연구자가 개발한 통증 불인정 코딩 매뉴얼에 따라 통증에 대한 무시 및 이해의 결여라는 2가지 요인으로 코딩하였다. 그 후, 사회적 제약, 우울, 외로움, 통증 관련 변인, 인구통계학적 변인 등에 대해 응답하게 했다. 분석 결과, 통증에 대한 불인정 반응은 사회적 제약을 높였고, 이것이 외로움을 거쳐 우울에 순차적으로 영향을 미치는 간접효과가 검증되었다. 본 연구는 그동안 질적 연구에 치우쳐 있던 통증 불인정과 사회적 제약, 외로움, 우울 변인과의 관계를 양적 연구로 검증했다. 또한, 만성통증 환자들의 심리적 건강을 증진하기 위해 환자들이 자신의 통증에 대해 마음껏 이야기할 수 있게 하는 지지적인 사회적 환경을 조성하는 것이 중요함을 다시 한번 환기함으로써, 다양한 후속 연구로 이어질 수 있는 발판을 마련했다는 점에서 의의가 있다.

Blockage in the ventral hippocampus with bupivacaine produces analgesia in the formalin pain test

Lee, Eun Jin 을지대학교 대학원 2022 국내박사

Pain, as defined by the International Association for the Study of Pain (IASP), is ‘‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’’. Pain is classified into ‘acute’ and ‘chronic’ pain based on the body part where the pain occurs and the cause and duration of the pain. There has been a considerable amount of researches on the transmission and modulation mechanisms of pain information from peripheral tissues to the central nervous system (CNS), on the progression of acute to chronic pain, and on the pharmacological management and drug development of the pain. It has also long been known that the CNS remembers painful experiences and it has been suggested that appropriate modulation of pain memory can improve the pain treatment. However, the understanding of the mechanism of pain memory is limited. In this study, the author have mapped ventral hippocampal bupivacaine-induced changes in the expression of the c-Fos protein in the rat brain. A subcutaneous injection of formalin into the plantar surface of the hind paws of the rat produces a bimodal nociceptive response including an early intense response in the first 5 min and a later moderate response that is exhibited from 20 to 60 min after injection. Animals were randomly divided into three groups; naive control group, artificial cerebrospinal fluid injection group (aCSF group), and bupivacaine injection group (bupivacaine group). In aCSF group and bupivacaine group, bupivacaine (0.5% w/v) and aCSF were injected through infusion pump for three weeks to the both ventral hippocampus (AP:-5.3 mm LAT: ±4.5 mm, dept: 7.8 mm) to block the ventral hippocampus. The blockade of the ventral hippocampus were checked through intracranial electroencephalogram (EEG). The hot plate test and formalin test were conducted to measure the potential anti-nociceptive effect of the ventral hippocampus block. The bupivacaine group showed a significant increase in latency response in hot plate test and showed a significant decrease in the number of pain responses (licking and flinching). These results indicated that the inhibition of pain memory formation in the ventral hippocampus relieves the pain perception by the experimental animals. Changes in c-Fos expression in various regions induced by pain stimulation following ventral hippocampal blockade were investigated through the immunohistochemical staining and analyzed through the semi-stereological cell counting analysis. The c-Fos expression level was significantly lowered in most brain areas which are known to be related with pain perception and modulation. In conclusion, the ventral hippocampus is involved in the experience, or expression, of persistent pain and the blockade of the circuit of the ventral hippocampus can influence tonic and/or chronic behavioral responses.

Patient-Related Factors to Pain Management among Mongolian Cancer Patients

바얄사이칸 서울대학교 대학원 2016 국내석사

Pain is one of the most common symptoms of cancer and approximately 25-75% of cancer patients experience pain. A patient who is experiencing pain plays an important role in identifying and assessing pain as well as in managing it. This study aimed to identify levels of anxiety, depression, beliefs on pain and analgesics, pain intensity, pain interference and adequacy of a pain management index and to examine their relationships among Mongolian cancer patients. A descriptive, cross-sectional design was used in this research. Data from convenience sampling of 145 cancer patients were collected from three hospitals and three hospices from February 19 to March 5, 2016. The independent t-test, one-way ANOVA, and Pearson’s correlation were performed using the SPSS 23.0 program. Among the participants, levels of both anxiety and depression were mild. Middle-aged patients were more anxious, while lung cancer patients, stage-IV cancer patients, and palliative care patients were more depressed. The highest concerns were fatalism, tolerance of analgesics, and monitoring disease progression. Patients who experienced cancer recurrence had fewer misbeliefs on pain and analgesics. Patients who were middle-aged, had completed high school education, lived in an urban setting, or were receiving hospice care reported higher levels of pain intensity and interferences. Patients who were religious or were receiving curative treatment had less pain intensity. High-income patients reported more pain interference. Fifty (34.4%) patients were under-treated for pain control, and they had higher rates of anxiety, depression, concern on immune system, fear of addiction, pain intensity, and pain interference. Patients who were female, non-religious, diagnosed with lung or cervical cancer, or were receiving curative treatment were more likely to be inadequately treated for pain control. As correlational study, patients who had higher levels of misbeliefs on pain and analgesics, pain intensity and interference were inadequately treated. The findings of the present study can be used to enhance effective communication between patients and their health professionals, provide guidance for educating patients on their illness and pain, and develop interventions to reduce patient-related factors influencing inadequate pain management. This study enriches knowledge in pain management among Mongolian cancer patients and may help health care providers and patients be aware of patient-related factors influencing pain management

Pain Management Among Dominican Patients with Advanced Osteoarthritis: A Qualitative Study

Yu, Amy Harvard University ProQuest Dissertations & Theses 2018 해외박사(DDOD)

Background: Advanced osteoarthritis and total joint replacement (TJR) recovery are painful experiences and often prompt opioid use in developed countries. Physicians participating in the philanthropic medical mission Operation Walk Boston (OpWalk) to the Dominican Republic have observed that Dominican patients require substantially less opioid medication following TJR than US patients. We conducted a qualitative study to investigate approaches to pain management and expectations for postoperative recovery in patients with advanced arthritis undergoing TJR in the Dominican Republic.Methods: We interviewed 20 patients before TJR about their pain coping mechanisms and expectations for postoperative pain management and recovery. Interviews were conducted in Spanish, translated, and analyzed in English using content analysis.Results: Patients reported modest use of pain medications and limited knowledge of opioids, and many relied on non-pharmacologic therapies and family support to cope with pain. They held strong religious beliefs that offered them strength to cope with chronic arthritis pain and prepare for acute pain following surgery. Patients exhibited a great deal of trust in powerful others, expecting God and doctors to cure their pain through surgery.Conclusion: We note the importance of understanding a patient’s individual pain coping mechanisms and identifying strategies to support these coping behaviors in pain management. Such an approach has the potential to reduce the burden of chronic arthritis pain while limiting reliance on opioids, particularly for patients who do not traditionally utilize powerful analgesics.

Multimodal approach for pain management : local analgesics, pharmacopuncture and time-restricted feeding

이정윤 서울대학교 대학원 2020 국내박사

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage by International Association for the Study of Pain (IASP). Since pain has both sensory-discriminative and affective-motivational dimensions, it is difficult to effectively modulate pain with a conventional pharmacological approach (NSAIDs and opioids) alone. In an effort to explore multimodal approaches to pain management, I have focused on the therapeutic effect of local analgesics (sinomenine), pharmacopuncture (acupoint stimulation with drug, Scolopendra subspinipes) and time-restricted feeding (fasting/refeeding) on animal pain models as below. In the first chapter, I revealed that sinomenine can produce peripheral analgesic effect by reducing cellular excitability of nociceptive neurons. The intraperitoneal injection of sinomenine suppressed formalin-induced pain behavior and c-Fos expression. Sinomenine inhibited voltage-gated sodium current in nociceptive neurons. Furthermore, the intraplantar injection of sinomenine also suppressed pain behavior. Therefore, sinomenine could be a potential pharmacological therapeutic agent for local anesthesia and analgesia. In the second chapter, I demonstrated that acupoint stimulation with Scolopendra subspinipes (pharmacopuncture with Scolopendra subspinipes, SSP) produces an analgesic effect via alpha2-adrenoreceptors in the spinal cord. SSP into Zusanli acupoint had a significant analgesic effect on oxaliplatin-induced neuropathic pain model. The intrathecal injection of yohimbine (alpha2-adrenoeceptor antagonist) reversed SSP-induced analgesic effect. Therefore, SSP produces an analgesic effect by activating descending pain inhibitory system, which suggests a possibility for pain management. In the third chapter, I focused on the analgesic effect of fasting and refeeding. Both 24h fasting and 2h refeeding produce analgesic effect but via different mechanisms, suggesting that endocannabinoid and opioid system is only involved in fasting-induced analgesia, whereas refeeding-induced analgesia is associated with eating behavior and calorie recovery effect. Therefore, the regulation of feeding (time-restricted feeding) may have abundant benefits to modulate pain and might provide a novel strategy for the management of pain. 통증은 국제 통증 연구 협회 (IASP)에 의해 실질적/잠재적 조직 손상과 관련된 불쾌한 감각 또는 정서적 경험으로 정의된다. 통증은 감각 및 정서적 요소를 모두 가지고 있기 때문에, 기존의 약리학적 접근법 (NSAID 및 오피오이드) 만으로는 통증을 효과적으로 조절하는 것이 어렵다. 따라서 본 학위 논문은 통증 관리에 대한 다각적인 접근 방식을 모색하기 위해 국소 진통제 (sinomenine), 약침 요법 (Scolopendra subspinipes, 오공 약침) 및 시간 제한 섭식 (금식 / 금식 후 재 섭식)의 통증 조절 가능성을 주요 연구 대상으로 하였다. 첫 번째 장에서는 sinomenine이 통각 수용 감각 신경의 흥분을 감소시킴으로써 말초에서 진통 효과를 유도 할 수 있음을 밝혔다. Sinomenine의 복강 내 투여는 포르말린으로 유도된 통증 행동 및 cFos 발현을 감소 시켰으며, sinomenine이 전압에 따라 개폐 되는 소디움 채널을 억제함을 통각 수용 감각신경에서 확인하였다. 또한 sinomenine을 하지 말단에 국소 투여하였을 때도 통증 행동 감소가 관찰되었다. 이러한 결과는 sinomenine이 국소 마취제 및 진통제로서 적용 가능함을 제시한다. 두 번째 장에서는 오공 약침을 이용한 경혈 자극이 척수에 존재하고 있는 alpha2 아드레날린 수용체를 통해 진통 효과를 유도한다는 것을 밝혔다. 오공약침을 족삼리 영역에 피하 투여 시 옥살리플라틴 처치로 인해 유발된 신경 병증성 통증을 감소시킴을 확인하였으며, alpha2 아드레날린 수용체의 길항제로 알려진 yohimbine을 척수 내에 주입하였을 때 오공 약침으로 유도된 진통 효과가 억제되었다. 따라서, 오공 약침에 의한 경혈 자극은 하행성 통증 억제 시스템을 활성화시켜 진통 효과를 나타내며, 이는 오공 약침을 이용한 통증 관리의 가능성을 시사한다. 세 번째 장에서는 금식과 재 섭식 시 보이는 진통 효과에 중점을 두었다. 자율 섭식과 비교하였을 때, 24 시간 금식과 2 시간 재섭식은 모두 진통 효과를 보였으나 진통 효과를 유도하는 기전이 다름을 확인하였다. 24 시간 금식 시 유도된 통증 억제 효과는 엔도카나비노이드와 오피오이드 시스템이 관여하는 반면, 2 시간 재섭식으로 유도된 진통 반응에는 섭식을 하는 행동 자체와 칼로리 회복이 관여 하였다. 따라서 섭식 조절 (시간 제한 섭식)은 통증 관리를 위한 새로운 치료 전략이 될 수 있을 것이라 기대된다.

Pain Management Strategies in Patients with Knee Osteoarthritis and Hypertension: Use, and Differences in Pain and Arthritis Pain Self-Efficacy

Shi, Xiaojun University of Pittsburgh ProQuest Dissertations & 2022 해외박사(DDOD)

Background: Chronic pain caused by knee osteoarthritis has a negative impact on patients’ quality of life. The prevalence of hypertension is high among patients with knee osteoarthritis, and usage of pain medications can increase patients’ blood pressure. Purpose: 1) Describe characteristics of pain and non pharmacological pain management strategies used by participants with knee osteoarthritis and hypertension in daily life; 2) Categorize pain management strategies and assess frequency and patterns of strategies patients used; and 3) Examine the effectiveness of pain management strategies on pain, and their relationship with pain self-efficacy. Method: This secondary analysis of data from a randomized controlled trial used qualitative and quantitative methods to address the aims. Seventy individuals from the 6-month intervention arm were included in this study. Qualitative data for Aims 1 and 2 were collected by semi-structured interview. Quantitative data for Aim 3 included participants’ knee pain, bodily pain, and pain self-efficacy, measured by Western Ontario and McMaster Universities Osteoarthritis Index, Short Form-36v2 Bodily Pain subscale, and Arthritis Pain Self-efficacy subscale, respectively, at baseline, immediate post-intervention, and 6 months post-intervention. Constant comparative and content analyses were used in Aims 1 and 2, respectively, to describe and summarize pain and pain management strategies that participants used. Linear mixed modeling was used in Aim 3 to assess differences in pain and pain self-efficacy for pain management strategies over time. Results: On average, participants employed five pain management strategies. The most commonly used strategies were practicing physical self-care activities, performing psychological self-care activities, being active, changing position, and avoiding overuse. Pain management strategies were categorized into treatment strategies only and both preventative and treatment strategies. Participants who only used treatment strategies reported significantly lower bodily pain (b=-7.94, p=.017) compared with participants who used both preventative and treatment strategies. A mediating effect of self-efficacy on the association between pain management strategies and pain was not found. Conclusion: Participants used multiple pain management strategies to control pain, and treatment strategies were favored, which health care providers can recommend to patients. Health care providers can suggest preventative strategies that are evidenced-based and that patients find effective to control their pain.

한방병원에 내원하는 파킨슨병 환자의 임상양상 및 통증에 관한 고찰 : 후향적 차트 리뷰

정혜선 경희대학교 대학원 2020 국내석사

Background : Parkinson's disease (PD) is a heterogeneous , progressive and neurodegenerative disease . Pain is one of frequently reported nonmotor symptoms in PD and inappropriately controlled pain can cause depression, diminished quality of life. There is a lack of attention to pain in PD because pain is relatively subjective symptom and main treatment of PD is focused on managing motor symptoms. There are no clear pain management guideline as well as each therapeutic realities have some limitations. While Study of pain in PD has been reported more and more, those studies were poorly documented in Korea. Objectives : To investigate prevalence of pain, pain characteristics, association between clinical features and pain, efficacy of Korean medical treatment for PD with pain. Methods : We performed a retrospective review of the medical records for patients diagnosed with Parkinson's disease between 2012 and 2019 at Gangdong kyunghee university korean medicine hosptal in South Korea. Results : Of 172 PD patients, 147 patients(85.5%) reported pain. Female PD patients more frequently reported pain than male(P=0.03). Sixty nine point three percent(69.3%) of patients complaining about musculoskeletal pain, and musculoskeletal pain show significant difference depending on the PD motor subtype(P=0.039). Pain was located mainly in the leg(57.8%) or back(34.7%). 22 patients with KPPS scores at least twice were analysed for evaluating efficacy of Korean medicine on pain in PD. Mean total scores before and after korean medical treatment were 15.23±11.01 and 9.2±8.7, respectively, and mean difference between before/after total scores was 6.0±5.8(P<0.001). Specifically, score of radicular pain was significantly decreased(P=0.048). Conclusions : In comparision with general population, PD patients has high prevelence of pain. This study suggests Korean Medicine could be beneficial for PD by reducing pain. For clinical efficacy, further study as a large-sample cohort study, RCTs should be done to clarify pathological pain relief mechanism and analgesic effect of Korean Medicine.

Pain modulation by recently deorphanized G-protein coupled receptors in DRG neurons

최승인 Graduate School, Korea University 2019 국내박사

Current analgesic strategies mostly depend on two traditional technologies, the opioid based ones and non-steroidal anti-inflammatory drugs (NSAID) and their variants. These two categories of analgesic strategies have many problems such as tolerance, dependence, addiction, gastrointestinal side effects, cardiovascular side effects, etc. Moreover NSAIDs have a low therapeutic efficacy on the pathologic pain, which indicates a huge demand for developing novel analgesic technologies. As these novel technologies, those that are believed to control the molecular targets on the neural pathway for pain sensation will be most effective at essentially blocking the generation and conduction of pain signals. In this context, the primary sensory nerves in the pain circuit are one of useful analgesic targets and seem to have a good access for external technologies because they have relatively thin blood brain barrier (BBB) compared to the higher brain region on the pain circuit. Since the identities of transient receptor potential (TRP) ion channels, a group of important pain receptor molecules, was revealed in the 1990s, the information of target molecules specifically expressed in primary nociceptors has been expanded, but it is still assumed that unknown receptors will exist in those types of neurons. These unknown receptors, when activated, are assumed to alter the excitability of the pain-specific primary sensory nerves by increasing or suppressing the activity of known pain mediators. When the functions of these unknown receptors can be controlled Effective analgesia may be achieved. Accordingly, my research aims to discover the unknown role of these types of receptors in the nociceptors among dorsal root ganglionic (DRG) neurons By analyzing the results of previous studies, a number of G-protein coupled receptors (GPRs), which are presumed to exhibit best DRG neuron-specific expression, were selected for this study. Among these GPRs, I further narrowed down the candidates for this study, which have been classified as orphan GPRs, but the identity of their ligands have been recently identified. Thus, I hypothesized that activation of GPR by their ligands would affect the excitability of nociceptors and cause an alteration of pain sensation. To verify this hypothesis at molecular, cellular, and individual levels, the following experiments were carried out: tissue expression studies, identification of intracellular signal transduction pathways, examination of basal intracellular receptor activity, and test of the in vivo pain effects. A series of experiments have shown that each GPR is expressed in pain-mediating DRG neurons and that it activates intracellular signaling by G𝛼i/o and G𝛼q proteins. In addition, in vivo pain behavioral tests with various mouse models demonstrated that the activation of one type of GPR caused excessive pain and that the activation of another type caused the suppression of pain. Based on the results, the present study confirmed the role of these GPRs at the molecular, cellular and individual levels and determined the possible impact when the activities of those GPRs are controlled on pain and its usefulness as an analgesic strategy. 현존하는 진통기술은 대부분 전통적인 양대 기술인 opioid 계열 기술과 비스테로이드성 소염제 기반 기술 (NSAID) 및 그 변형에 불과하다. 이 두 기술은 내성, 의존성, 탐닉성, 위장관계 부작용, 심혈관계 부작용 등의 문제점을 안고 있으며, NSAID는 질환적 통증에는 치료효과가 낮아 새로운 진통기술의 개발이 시급하다. 이러한 새로운 진통기술로서, 통증신경경로 상 발현하는 분자표적을 제어하여 근본적인 통증신호 발발과 전도를 차단하는 기술이 가장 효과적일 것이라 여겨진다. 통증신경경로 중 1차 감각신경은 특정 자극에 대해 활성을 보이는 기질특이성을 가짐과 동시에 혈뇌장벽이 없거나 얇아 기술 접근성이 좋은 장점을 가지고 있어 진통표적으로 유용하다. 90년대 들어 통각수용체의 일종인 TRP channel들의 정체가 밝혀진 이후로 현재까지 1차감각신경에 특이적으로 발현하는 표적분자 정보가 확충되고 있으나, 여전히 미지의 수용체가 존재할 것으로 추측되고 있다. 이들 미지의 수용체는, 활성화되었을 경우 알려진 통증매개 분자들의 활성을 증진시키거나 억제함으로써 1차 감각 신경의 흥분도를 변화시킬 것으로 추측되므로, 이 수용체를 제어하여 궁극적으로 진통 목적을 구현할 수 있으리라 예상된다. 이에 따라 본 연구에서는 1차 감각신경 세포인 뒤뿌리 신경세포 (dorsal root ganglionic neuron; DRG neuron) 중 통각신경세포 (nociceptor)에 집중적으로 분포하고 있는 미지의 수용체를 발굴하고 그 역할을 규명하였다. 연구대상으로, 선행연구결과를 분석하여 가장 우수한 통각신경세포 특이적 발현을 보일 것으로 추정되는 G-단백질 연결 수용체 (G-protein coupled receptor, GPR)를 선정하였다. 이들 GPR은 ligand의 정체가 규명되지 않은 소위 orphan GPR로 분류되어 왔는데, 최근 신규 ligand가 제기된 바 있다. 따라서 본 연구에서는 이들 신규 ligand에 의한 GPR 활성화가 통각신경세포의 흥분도에 영향을 미쳐 통각변화를 일으킬 것이라 가설을 세웠다. 이 가설을 분자, 세포 및 개체 수준에서 검증하기 위하여, 조직 발현도 조사, 세포 내 신호전달과정 규명, 기존 통각수용체 활성도 제어 여부 규명, 개체 통증행동 변화 검정 등을 실시하였다. 연구 결과, 각 GPR은 통각신경세포에 발현하고 있으며 G𝛼i/o 및 G𝛼q 단백질에 의한 세포 내 신호전달과정을 활성화시키는 것으로 나타났다. 또한 분자, 세포 및 개체 수준에서 이들 GPR의 역할 검정 연구를 완성하여 통증에 미치는 영향과 진통표적으로서의 유용성을 확인하였다.

Developing neuroimaging biomarker for sustained experimental and clinical pain

Lee, Jaejoong Sungkyunkwan University 2023 국내박사

Understanding neurobiological mechanisms of pain has enormous implications for basic science and clinical practices. However, the subjectivity and ambiguity of the measurement of pain have hampered its progress. This dissertation presents a series of attempts to develop brain-based biomarkers that can quantitatively and objectively measure subjective pain using functional magnetic resonance imaging (fMRI), with particular focus on the sustained pain which is a hallmark of clinical pain disorders. In Chapter 1, we reviewed the emergence of predictive modeling and graph-theoretical approach from the history of pain research, and highlighted the translational potential of experimentally-induced sustained pain. In Chapter 2 and 3, we introduced the actual application of these approaches based on fMRI data. In the Chapter 2, we used whole-brain functional connectivity to develop a biomarker that can predict ongoing sustained pain induced by orofacial capsaicin. This biomarker not only showed high sensitivity and specificity across multiple capsaicin pain fMRI datasets but also could be generalized onto clinical back pain fMRI datasets as well, suggesting the shared neural mechanisms across sustained experimental and clinical pain. In the Chapter 3, we used graph-theoretical analyses to examine how functional brain architecture was reconfigured over the experience of sustained pain induced by orofacial capsaicin. The characteristic features of dynamic brain reconfiguration were then used to develop biomarkers predictive of sustained pain, which also demonstrated significant sensitivity and specificity. Overall, these results provide new insight into the brain mechanisms of sustained pain, and ultimately contribute to the development of clinically useful objective biomarkers of pain. 만성 통증 연구 및 치료는 그 막대한 중요성과 사회적 함의에도 불구하고 측정 대상이 되는 통증 자체의 주관성과 모호함 때문에 많은 어려움이 있어왔다. 본 연구에서는 실험적으로 유발된 지속적 통증과, 임상에서 진단된 만성 통증 질환을 대상으로 뇌 기능 영상을 통해 신경생물학적 기전을 규명하고 통증을 객관적으로 측정할 수 있는 생물학적 표지자를 개발하고자 한다. 1장에서는 통증 연구의 역사적인 흐름에서, 전체 뇌의 분산된 기능을 반영하는 기법으로서의 예측 모델링과 그래프 이론적 접근의 출현을 검토하고, 실험적으로 유도된 만성 통증의 임상적 중개 가능성을 서술한다. 이어지는 2장과 3장에서는 위의 두 가지 방법론의 뇌 기능 영상 데이터에서의 실제적 적용을 다룬다. 2장에서는 전체 뇌의 기능적 연결성을 사용하여 캡사이신에 의해 유도된 지속적인 구강안면 통증을 예측할 수 있는 바이오마커를 개발했다. 이 바이오마커는 여러 캡사이신 통증 데이터셋에 걸쳐 높은 민감도와 특이도를 보여줬을 뿐만 아니라 임상적 허리 통증을 예측하는 데에도 우수한 성능을 나타냈으며, 이는 본 바이오마커가 실험적 및 임상적 통증에 공통적인 신경생물학적 기전을 반영함을 시사한다. 3장에서는 그래프 이론을 사용하여 캡사이신에 의해 유발된 지속적 통증에 따른 기능적 뇌 네트워크의 동적인 재구성을 확인했다. 또한, 통증 변화에 따른 뇌 네트워크의 특징적인 변화의 패턴을 기반으로 지속적 통증의 세기를 예측하는 바이오마커를 개발하였으며 이 바이오마커는 높은 민감도와 특이도를 보여주었다. 본 결과는 실험적 및 임상적 만성 통증의 뇌 메커니즘에 대한 새로운 통찰을 제공하며, 궁극적으로 임상적으로 유용한, 객관적인 통증 바이오마커 개발에 기여할 것으로 기대된다.