scholarly journals Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission

2021 ◽  
Author(s):  
Alan Prossin ◽  
Alisa Koch ◽  
Phillip Campbell ◽  
Geoffroy Laumet ◽  
Christian S. Stohler ◽  
...  
Keyword(s):  
Endogenous Opioid ◽  
Healthy Human ◽  
Pain Scores ◽  
Neuroimmune Interactions ◽  
Positron Emission ◽  
Pet Scanning ◽  
Human Volunteers ◽  
Μ Opioid Receptor ◽  
Inflammatory Proteins ◽  
Pet Scans

AbstractBehavioral conditioning and expectation can have profound impact on animal and human physiology. Placebo, administered under positive expectation in clinical trials, can have potent effects on disease pathology, obscuring active medications. Emerging evidence suggests placebo-responsive neurotransmitter systems (e.g., endogenous opioid) regulate immune function by manipulating inflammatory proteins including IL-18, a potent pro-inflammatory, nociceptive cytokine implicated in pathophysiology of various diseases. Validation that neuroimmune interactions involving brain μ-opioid receptor (MOR) activity and plasma IL-18 underlie placebo analgesic expectation could have widespread clinical applications. Unfortunately, current lack of mechanistic clarity obfuscates clinical translation. To elucidate neuroimmune interactions underlying placebo analgesia, we exposed 37 healthy human volunteers to a standardized pain challenge on each of 2 days within a Positron Emission Tomography (PET) neuroimaging paradigm using the MOR selective radiotracer, 11C-Carfentanil (CFN). Each day volunteers received an intervention (placebo under analgesic expectation or no treatment), completed PET scanning, and rated their pain experience. MOR BPND parametric maps were generated from PET scans using standard methods. Results showed placebo reduced plasma IL-18 during pain (W74 = −3.7, p < 0.001), the extent correlating with reduction in pain scores. Placebo reduction in IL-18 covaried with placebo-induced endogenous opioid release in the left nucleus accumbens (T148 = 3.33; puncorr < 0.001) and left amygdala (T148 = 3.30; puncorr < 0.001). These findings are consistent with a modulating effect of placebo (under analgesic expectation in humans) on a potent nociceptive, pro-inflammatory cytokine (IL-18) and underlying relationships with endogenous opioid activity, a neurotransmitter system critically involved in pain, stress, and mood regulation.

scholarly journals Acute acetate administration increases endogenous opioid levels in the human brain: A [11C]carfentanil molecular imaging study

2021 ◽  
pp. 026988112096591
Author(s):  
Abhishekh H Ashok ◽  
Jim Myers ◽  
Gary Frost ◽  
Samuel Turton ◽  
Roger N Gunn ◽  
...  
Keyword(s):  
Human Brain ◽  
Sodium Acetate ◽  
Statistical Significance ◽  
Imaging Study ◽  
Pet Scan ◽  
Endogenous Opioid ◽  
Reference Tissue ◽  
Healthy Human ◽  
Fourfold Increase ◽  
Positron Emission

Introduction: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. Methods: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. Results: Following sodium acetate administration, 2.5–6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. Conclusions: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

scholarly journals Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

2016 ◽  
Vol 37 (3) ◽  
pp. 1095-1107 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Beata Planeta ◽  
Nabeel Nabulsi ◽  
Donna Palumbo ◽  
Xiaoxi Li ◽  
...  
Keyword(s):  
Binding Sites ◽  
Human Subjects ◽  
Receptor Occupancy ◽  
Healthy Human ◽  
Positron Emission ◽  
Relationship Of ◽  
The Relationship ◽  
Pet Scans

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites ( ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher.

6-[ 18 f]Fluorodopamine Positron Emission Tomographic (PET) Scanning in the Diagnostic Localization of Pheochromocytoma

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 714-715
Author(s):  
David S Goldstein ◽  
Graeme Eisenhofer ◽  
Sheng-Ting Li ◽  
Karel Pacak
Keyword(s):  
Nuclear Imaging ◽  
High Sensitivity ◽  
Good Sensitivity ◽  
Positron Emission Tomographic ◽  
Resonance Imaging ◽  
Positron Emission ◽  
Pet Scanning ◽  
Pet Scans ◽  
Initial Results ◽  
Limited Sensitivity

P119 The diagnosis and treatment of pheochromocytoma (PHEO) depend on means to localize the tumor. Computed tomography and magnetic resonance imaging have good sensitivity but poor specificity, and nuclear imaging has limited sensitivity. Here we report initial results of 6-[ 18 F]Fluorodopamine PET scanning in patients with known or suspected PHEO. Of 23 patients, 13 had the tumor. Ten had normal plasma levels of metanephrines, excluding PHEO. All 13 patients with PHEO had abnormal fluorodopamine PET scans that identified the tumors. The 10 patients without PHEO had negative PET scans. Fluorodopamine PET scanning detects PHEO with high sensitivity.

Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

2005 ◽  
Vol 103 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Vincent Joly ◽  
Philippe Richebe ◽  
Bruno Guignard ◽  
Dominique Fletcher ◽  
Pierre Maurette ◽  
...  
Keyword(s):  
Large Dose ◽  
Small Dose ◽  
Detection Threshold ◽  
Skin Closure ◽  
Cognitive Tests ◽  
Secondary Hyperalgesia ◽  
Healthy Human ◽  
Pain Scores ◽  
Human Volunteers ◽  
Quantitative Sensory Tests

Background Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia. Methods Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 microg x kg(-1) x min(-1) (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 microg x kg(-1) x min(-1) until skin closure and then 2 microg x kg(-1) x min(-1) for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h. Results Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P &lt; 0.05) and allodynia to von Frey hair stimulation was greater (P &lt; 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects. Conclusion A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-d-aspartate pain-facilitator process.

Use of 18F-choline and 11C-choline as contrast agents in positron emission tomography imaging—guided stereotactic biopsy sampling of gliomas

2003 ◽  
Vol 99 (3) ◽  
pp. 474-479 ◽  
Author(s):  
Toshihiko Hara ◽  
Tatsuya Kondo ◽  
Tetsuo Hara ◽  
Noboru Kosaka
Keyword(s):  
Positron Emission Tomography ◽  
Contrast Agents ◽  
Anaplastic Astrocytoma ◽  
Stereotactic Biopsy ◽  
Emission Tomography ◽  
Content Type ◽  
Positron Emission ◽  
Pet Scanning ◽  
Pet Scans ◽  
Fine Print

Object. Neuroimaging-guided stereotactic biopsy procedures are commonly used for diagnosis of gliomas. A number of the imaging modalities currently in use are not reliable enough in depicting these tumors. The authors developed 18F-choline and 11C-choline as tumor imaging agents for positron emission tomography (PET) scanning, and used them to visualize gliomas prior to stereotactic biopsy procedures. Methods. The PET studies were performed in 12 patients who were thought to be affected by gliomas observed on computerized tomography and magnetic resonance images. The 18F- and 11C-choline were injected separately, and the PET scanning was started 5 and 20 minutes postinjection. The PET scans gave quantitative information about the distribution of 18F- and 11C-choline in the brain. The tumor uptake was constant between 5 and 20 minutes with both agents. Stereotactic biopsy sampling was performed to obtain tissues from the most radioactive areas on the PET scan; histological diagnoses were made using these tissues. The results were as follows: oligodendroglioma was found in two patients, astrocytoma in one, anaplastic astrocytoma in two, and glioblastoma in seven. Conclusions. The uptake of contrast agents was always low in low-grade gliomas, and the uptake in high-grade glioma was always high. The tumor/normal (T/N) ratio of 18F-choline was 10.5:12 in anaplastic astrocytoma and 13.2:21 in glioblastoma. The 18F-choline yielded slightly superior results compared with 11C-choline with regard to the T/N ratio. In one case of oligodendroglioma the tumor showed no uptake of 18F- and 11C-choline. With this exception, the PET scans of gliomas in which 18F- and 11C-choline contrast agents were added would guide the approach to the most malignant areas for stereotactic biopsy sampling.

Positron Emission Tomography in Head and Neck Oncology

1995 ◽  
Vol 112 (5) ◽  
pp. P130-P130
Author(s):  
W. Frederick McGuirt
Keyword(s):  
Positron Emission Tomography ◽  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Emission Tomography ◽  
Head And Neck Oncology ◽  
Educational Objectives ◽  
Positron Emission ◽  
Pet Scanning ◽  
Pet Scans

Educational objectives: To understand the principles and technique of positron emission tomography (PET) scanning and to know when PET scans will be beneficial in the evaluation of patietns with head and neck cancer.

Comparison of Positron Emission Tomography Scanning and Sentinel Node Biopsy in the Detection of Micrometastases of Primary Cutaneous Malignant Melanoma

2001 ◽  
Vol 19 (10) ◽  
pp. 2674-2678 ◽  
Author(s):  
K.M. Acland ◽  
C. Healy ◽  
E. Calonje ◽  
M. O’Doherty ◽  
T. Nunan ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Sentinel Node ◽  
Fdg Pet ◽  
Primary Melanoma ◽  
Emission Tomography ◽  
Micrometastatic Disease ◽  
Node Biopsy ◽  
Positron Emission ◽  
Pet Scanning ◽  
Pet Scans

PURPOSE: Sentinel node biopsy (SNB) is a surgical technique for detecting micrometastatic disease in the regional draining nodes. 2-fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scanning is an imaging technique that can detect clinically undetectable metastases. This prospective study was undertaken to compare the sensitivity of FDG-PET scanning with SNB in the detection of micromatastatic malignant melanoma. PATIENTS AND METHODS: Fifty consecutive patients (23 women, 27 men; mean age, 53 years) with primary melanoma >1 mm thick or lymphatic invasion were recruited (mean, 2.41 mm). Primary lesions had been narrowly excised (<1 cm). Patients underwent PET scanning followed by SNB, using a dual technique. Preoperative lymphoscintigraphy was used to identify the draining basin. Lymph nodes were examined histologically and immunostained for S100 and HMB 45. RESULTS: The sentinel node (SN) was identified in all patients. Fourteen patients (28%) had positive SNBs, including eight patients with melanoma <1.5 mm thick. In none of these 14 patients did PET scans identify metastatic disease in the SN or draining basin. In seven patients, the PET scans were positive in other locations, and in four cases, this was suspicious of metastatic disease. However, no patient has developed recurrent melanoma (mean follow-up, 15 months). All patients with positive SNBs underwent therapeutic lymph node dissection. Further lymph node involvement was found in two patients (primary lesions, 1.3 mm and 3.5 mm thick). CONCLUSION: This study demonstrates the limitations of FDG-PET scanning in staging patients with primary melanoma. SNB is the only reliable method for identifying micrometastatic disease in the regional draining node.

scholarly journals Mesolimbic opioid-dopamine interaction is disrupted in obesity but recovered by weight loss following bariatric surgery

2020 ◽  
Author(s):  
Henry K. Karlsson ◽  
Lauri Tuominen ◽  
Semi Helin ◽  
Paulina Salminen ◽  
Pirjo Nuutila ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Weight Loss ◽  
Ventral Striatum ◽  
Morbidly Obese ◽  
Obese Women ◽  
Link Type ◽  
Positron Emission ◽  
Pet Scanning ◽  
Μ Opioid Receptor ◽  
Obese Subjects

AbstractBackgroundObesity is a growing burden to health and economy worldwide. Obesity is associated with central μ-opioid receptor (MOR) downregulation, and the interaction between MOR and dopamine D2 receptor (D2R) system in the ventral striatum is disrupted among obese subjects. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying subjects undergoing surgical weight loss (bariatric surgery) procedure.MethodsWe recruited 20 healthy non-obese (mean BMI 22) and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and D2R availability was measured using positron emission tomography (PET) with [11C]carfentanil and [11C]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed to obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery.ResultsIn the control subjects, MOR and D2R availabilities were associated in the ventral striatum (r = .62) and dorsal caudate (r = .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r = .12) but unaltered association in dorsal caudate (r = .43). The association between MOR and D2R availabilities in the ventral striatum was recovered (r = .62) among obese subjects following the surgery-induced weight loss (mean total weight loss 22 %).ConclusionsBariatric surgery and concomitant weight loss recovers the interaction between MOR and D2R in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioural interventions for treating obesity.Clinical Trials RegistrationSleevePET2, NCT01373892, http://www.clinicaltrials.gov

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