Comparison of NASA-TLX scale, modified Cooper-Harper scale and mean inter-beat interval as measures of pilot mental workload during simulated flight tasks.

The sensitivity of NASA-TLX scale, modified Cooper-Harper (MCH) scale and the mean inter-beat interval (IBI) of successive heart beats, as measures of pilot mental workload (MWL), were evaluated in a flight training device (FTD). Operational F/A-18C pilots flew instrument approaches with varying task loads. Pilots' performance, subjective MWL ratings and IBI were measured. Based on the pilots' performance, three performance categories were formed; high-, medium- and low-performance. Values of the subjective rating scales and IBI were compared between categories. It was found that all measures were able to differentiate most task conditions and there was a strong, positive correlation between NASA-TLX and MCH scale. An explicit link between IBI, NASA-TLX, MCH and performance was demonstrated. While NASA-TLX, MCH and IBI have all been previously used to measure MWL, this study is the first one to investigate their association in a modern FTD, using a realistic flying mission and operational pilots. Practitioner summary: NASA-TLX scale, MCH scale and the IBI were evaluated in a flight training device. All measures were able to differentiate most task conditions and there was a positive correlation between NASA-TLX and MCH scale. An explicit link between IBI, NASA-TLX, MCH and performance was demonstrated. Abbreviations: ANOVA: Analysis of Variance; ECG: Electrocardiograph; F/A: fighter/attack; ft: feet; FTD: flight training device; G: Gravity; km: kilometer; m: meter; m/s: meters per second; MWL: mental workload; MCH: modified cooper-harper; NASA-TLX: NASA Task Load Index; NM: Nautical Mile; NN: normal-to-normal; IBI: inter-beat interval; ILS: Instrument Landing System; RR: R-Wave to R-Wave; SD: standard deviation; TTP: tactics, techniques and procedures; WTSAT: Weapon Tactics and Situation Awareness Trainer.

Dual inhibition of tumour necrosis factor and interleukin-17A with ABT-122: open-label long-term extension studies in rheumatoid arthritis or psoriatic arthritis.

Objectives: To evaluate the safety and maintenance of efficacy with ABT-122, a bi-specific monoclonal antibody targeting TNF and IL-17A, in patients with RA or PsA in open-label, 24-week extensions [open-label extensions (OLEs)] of 12-week, randomized, double-blind studies. Methods: All patients received ABT-122 (RA, 120 mg; PsA, 240 mg) subcutaneously every other week on background MTX. Safety assessments included adverse events (AEs) and laboratory parameters. Efficacy was evaluated with ACR responses, 28-joint DAS using high-sensitivity CRP [DAS28 (hsCRP)], and Psoriasis Area and Severity Index (PsA study). Results: The RA OLE study enrolled 158 patients; the PsA OLE study enrolled 168 patients. In the RA OLE study, the incidence of treatment emergent AEs (TEAEs; 41%) appeared similar to the double-blind study (36-43%). In the PsA OLE study, 57% of patients reported ⩾1 TEAE (double-blind study, 42-53%). Most TEAEs were mild or moderate in severity. There were no neutrophil abnormalities greater than grade 2. Grade 3 and/or 4 laboratory abnormalities were reported for lymphocytes, alanine aminotransferase, aspartate aminotransferase, bilirubin and haemoglobin; the number of these severe laboratory values was low (0.6-3.0%), except grade 3 lymphocyte count decreased (11.5%) in the RA study. In both OLE studies, efficacy assessed by ACR responses and other disease activity scores was maintained over the 24 weeks. Conclusion: ABT-122 demonstrated acceptable tolerability and maintenance of efficacy for up to 36 weeks in patients with RA or PsA receiving background MTX. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02433340 and NCT02429895.

Fighter pilots' heart rate, heart rate variation and performance during instrument approaches.

Fighter pilots' heart rate (HR), heart rate variation (HRV) and performance during instrument approaches were examined. The subjects were required to fly instrument approaches in a high-fidelity simulator under various levels of task demand. The task demand was manipulated by increasing the load on the subjects by reducing the range at which they commenced the approach. HR and the time domain components of HRV were used as measures of pilot mental workload (PMWL). The findings of this study indicate that HR and HRV are sensitive to varying task demands. HR and HRV were able to distinguish the level of PMWL after which the subjects were no longer able to cope with the increasing task demands and their instrument landing system performance fell to a sub-standard level. The major finding was the HR/HRV's ability to differentiate the sub-standard performance approaches from the high-performance approaches. Practitioner Summary: This paper examined if HR and HRV were sensitive to varying task demands in a fighter aviation environment and if these measures were related to variations in pilot's performance.

Accuracy and Similarity of Team Situation Awareness in Simulated Air Combat.

BACKGROUND: Fighter pilots' Team Situation Awareness (TSA) has been studied from the perspective of TSA accuracy, which represents how closely the pilots' collective knowledge is aligned with the real world. When TSA accuracy is low, the pilots can have similarly or dissimilarly inaccurate SA. The concept of TSA similarity represents the similarity of team members' collective knowledge. This paper investigates how TSA accuracy and similarity of F/A-18 pilots are associated with performance.METHOD: Data were extracted from simulated air combat missions. Performance and TSA were investigated in 58 engagements. The accuracy and similarity of pilots' SA were elicited and performance was evaluated. TSA accuracy and similarity were analyzed with respect to the flights' performance, and the independent variables were events in which the flights initiated engagements with enemy aircraft versus events in which the flights were engaged by enemy aircraft.RESULTS: With the mentioned events as the main effect, there were statistically significant differences at all levels of TSA accuracy and similarity. With performance as the main effect, there were also significant differences at all levels of TSA accuracy and similarity. TSA accuracy and similarity were superior in offensive engagements and when engagements were successful.DISCUSSION: The main contribution of this paper is the extension of the concept of TSA similarity to air combat: both TSA similarity and accuracy were higher when the flight was engaging the enemy aircraft, compared to situations when the flight itself was being engaged. The results also suggest that low TSA accuracy and similarity have a statistically significantly negative impact on the flights' performance.Mansikka H, Harris D, Virtanen K. Accuracy and similarity of team situation awareness in simulated air combat. Aerosp Med Hum Perform. 2023; 94(6):429-436.

Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study.

BACKGROUND: The inhaled corticosteroid (ICS) fluticasone propionate (fluticasone) and the long-acting ß2-agonist (LABA) formoterol fumarate (formoterol) are being made available as a combination product (fluticasone/formoterol, flutiform ®) in a single aerosol inhaler. This 12-week, open-label, randomized, active-controlled, parallel-group, multicentre, phase 3 study compared the efficacy and safety of fluticasone/formoterol with the commercially available combination product fluticasone/salmeterol. METHODS: Patients aged ≥ 18 years (N = 202) with mild-to-moderate-severe, persistent asthma for ≥ 6 months prior to screening were included in the study. After a screening phase (4-10 days), eligible patients were randomized 1:1 to receive fluticasone/formoterol or fluticasone/salmeterol during the 12-week treatment period. The primary objective was to demonstrate non-inferiority of fluticasone/formoterol versus fluticasone/salmeterol, measured by pre-dose forced expiratory volume in the first second (FEV1), at week 12. RESULTS: Fluticasone/formoterol was comparable to fluticasone/salmeterol for the primary efficacy endpoint, mean pre-dose FEV1 at week 12. The new combination was also comparable to fluticasone/salmeterol for change from baseline to week 12 in pre-dose FEV1, change from pre-dose FEV1 at baseline to 2-hour post-dose FEV1 at week 12 and discontinuations due to lack of efficacy. Importantly, fluticasone/formoterol was superior to fluticasone/salmeterol in time to onset of action throughout the duration of the study. The two treatments demonstrated similar results for various other secondary efficacy parameters, including other lung function tests, patient-reported outcomes, rescue medication use, asthma exacerbations and Asthma Quality of Life Questionnaire scores. Fluticasone/formoterol was well tolerated and had a good safety profile that was similar to fluticasone/salmeterol. CONCLUSIONS: The results of this study indicate that fluticasone/formoterol is as effective as fluticasone/salmeterol, and has a more rapid onset of action, reflecting the faster bronchodilatory effects of formoterol compared with those of salmeterol. If patients perceive the benefits of therapy with fluticasone/formoterol more rapidly than with fluticasone/salmeterol, this could have a positive impact on preference and adherence.

Team situation awareness accuracy measurement technique for simulated air combat - Curvilinear relationship between awareness and performance.

A new technique for the assessment of Team Situation Awareness (TSA) accuracy based upon post task Critical Decision Method structured interviews was developed and tested using 39 combat-ready F/A-18 pilots. Pilots undertook a number of simulated air combat scenarios, flying in flights of four aircraft against a formation of enemy aircraft. Results showed a strong curvilinear relationship where high TSA accuracy resulted in higher performance in some areas of air combat, measured with friendly losses and kills. There were diminishing returns in performance as TSA accuracy increased. This may explain why previous studies on air combat have found relatively weak relationships between situation awareness and performance where the relationship has been assumed to be linear.

Normative Performance Measurement in Simulated Air Combat.

BACKGROUND: Normative performance (NP) describes the pilots adherence to tactics, techniques, and procedures (TTPs). Until now, there has not been a global NP measurement technique for beyond visual range (BVR) air combat, and the methodology and technology related to the evaluation of NP have fallen behind the pace of the overall technical progress of distributed mission operations (DMO) training.METHODS: Platform-independent core air combat tasks were identified. The execution of these tasks is directed with TTPs. BVR air combat missions were flown in a DMO simulator system and the design NP was varied between missions. Observers viewed debriefs of these missions and attempted to identify TTP-regulated air combat tasks. Once identified, they scored the pilots NP in those tasks. The scoring was based on the level of TTP adherence and the impact a nonadherence had on the mission accomplishment.RESULTS: All observers were able to identify most of the TTP-regulated air combat tasks. There was a strong positive correlation between the observed and design NP scores. The overall Kappa indicated a fair agreement between the observers. The percentage of observers NP assessments which agreed with the design NP varied from 49.60 to 85.28% in different air combat missions. On average, 73.9%6 of the observers NP scores agreed with the design NP scores.CONCLUSIONS: Observers were able to accurately identify TTP-regulated tasks and score NP of these tasks during an air combat debrief. There was a moderate agreement between the observers NP scores.Mansikka H, Virtanen K, Mkinen L, Harris D. Normative performance measurement in simulated air combat. Aerosp Med Hum Perform. 2021; 92(11):908-912.

Idiopathic distal sensory polyneuropathy: ACTTION diagnostic criteria.

OBJECTIVE: To present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research. METHODS: The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria. RESULTS: An iDSP diagnosis requires at least 1 small fiber (SF) or large fiber (LF) symptom, at least 1 SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intraepidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least 1 of the above clinical features is SF and 1 clinical feature is LF with abnormalities in sensory NCS or IENFD. Diagnostic criteria for iSFN require at least 1 SF symptom and at least 1 SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least 1 LF symptom and at least 1 LF sign with normal IENFD, abnormal sensory NCS, and absence of SF symptoms and signs. CONCLUSION: Adoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs.

Pharmacokinetics of ABT-122, a TNF-α- and IL-17A-Targeted Dual-Variable Domain Immunoglobulin, in Healthy Subjects and Patients with Rheumatoid Arthritis: Results from Three Phase I Trials.

BACKGROUND AND OBJECTIVE: ABT-122 is a dual-variable domain immunoglobulin that neutralizes both tumor necrosis factor-α and interleukin-17A, with the goal of achieving greater clinical efficacy than can be achieved by blocking either cytokine alone. This work characterized the pharmacokinetics of ABT-122 in healthy subjects and in patients with rheumatoid arthritis. METHODS: ABT-122 pharmacokinetics was evaluated in three phase I studies. In Study 1, single intravenous (0.1, 0.3, 1, 3, and 10 mg/kg) and subcutaneous (0.3, 1, and 3 mg/kg) doses were evaluated in healthy subjects. In Studies 2 and 3, multiple subcutaneous doses (1 mg/kg every other week or 0.5-3 mg/kg every week) were evaluated for 8 weeks in patients with rheumatoid arthritis on stable methotrexate therapy. Pharmacokinetic data were available from 48 healthy subjects and 31 patients with rheumatoid arthritis. RESULTS: ABT-122 showed multi-exponential disposition with more than dose-proportional exposures at the 0.1-1 mg/kg doses and approximately dose-proportional exposures at doses ≥1 mg/kg. ABT-122 absolute subcutaneous bioavailability was approximately 50% with maximum serum concentrations observed 3-4 days after dosing. Steady state was achieved by week 6 of subcutaneous dosing. ABT-122 maximum serum concentration-to-trough concentration ratio was 2.6 for every other week dosing and 1.3 for every week dosing, corresponding to an effective half-life of 10-18 days. ABT-122 median area under the serum concentration-time curve accumulation ratio was 3.8-4.8 with every week dosing. Measureable antidrug antibodies were observed in all 48 subjects in Study 1 by day 15 post-dose and 19 of 31 ABT-122-treated patients in Studies 2 and 3 [median time to appearance of antidrug antibodies of 64 days (range 15-92 days)]. No dose-limiting toxicities were observed in these studies and the maximum tolerated dose was not identified. CONCLUSIONS: Results from these three phase I studies supported testing ABT-122 every week and every other week regimens in phase II trials in subjects with rheumatoid and psoriatic arthritis. Study 2 (EudraCT: 2012-003448-54); Study 3 (NCT01853033).

ABT-122, a Bispecific Dual Variable Domain Immunoglobulin Targeting Tumor Necrosis Factor and Interleukin-17A, in Patients With Rheumatoid Arthritis With an Inadequate Response to Methotrexate: A Randomized, Double-Blind Study.

OBJECTIVE: Tumor necrosis factor (TNF) and interleukin-17A (IL-17A) may independently contribute to the pathophysiology of rheumatoid arthritis (RA). This study sought to evaluate the safety and efficacy of ABT-122, a novel dual variable domain immunoglobulin targeting human TNF and IL-17A, in patients with RA who have experienced an inadequate response to methotrexate. METHODS: Patients with active RA who were receiving treatment with methotrexate and had no prior exposure to biologic agents (n = 222) were enrolled in a 12-week phase II randomized, double-blind, active-controlled, parallel-group study. Patients were randomized to receive either ABT-122 at dosages of 60 mg every other week, 120 mg every other week, or 120 mg every week or adalimumab at 40 mg every other week, administered subcutaneously. The primary efficacy end point was the proportion of patients achieving a ≥20% improvement response based on the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. RESULTS: Treatment-emergent adverse events were similar across all treatment groups, with no serious infections or systemic hypersensitivity reactions reported with ABT-122. ACR20 response rates at week 12 were 62%, 75%, and 80% with ABT-122 60 mg every other week, 120 mg every other week, and 120 mg every week, respectively, compared with an ACR20 response rate of 68% with 40 mg adalimumab every other week. The corresponding response rates for ACR50 and ACR70 improvement in the ABT-122 dose groups and adalimumab group were 35%, 46%, 47%, and 48%, respectively, and 22%, 18%, 36%, and 21%, respectively. CONCLUSION: Over the 12-week study period, dual inhibition of TNF and IL-17A with ABT-122 produced a safety profile consistent with that of adalimumb used for inhibition of TNF alone. The efficacy of ABT-122 over 12 weeks at dosages of 120 mg every other week or 120 mg every week was not meaningfully differentiated from that of adalimumab at a dosage of 40 mg every other week in patients with RA receiving concomitant methotrexate.

Phase II Study of ABT-122, a Tumor Necrosis Factor- and Interleukin-17A-Targeted Dual Variable Domain Immunoglobulin, in Patients With Psoriatic Arthritis With an Inadequate Response to Methotrexate.

OBJECTIVE: To investigate the safety and efficacy of ABT-122, a tumor necrosis factor (TNF)- and interleukin-17A (IL-17A)-targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) who have experienced an inadequate response to methotrexate. METHODS: Patients (n = 240) were randomized to receive ABT-122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12-week double-blind, parallel-group study. The primary efficacy end point was the proportion of patients achieving ≥20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 12. Secondary and exploratory 12-week end points included 50% improvement (ACR50) and 70% improvement (ACR70) response rates, and proportion of patients meeting the Psoriasis Area and Severity Index (PASI) response criteria for ≥75% (PASI75) and ≥90% (PASI90) improvement in skin scores among those with ≥3% of their body surface area affected by psoriasis. RESULTS: In both ABT-122 dose groups, ACR20 response rates at week 12 (64.8-75.3%) were superior to that in patients receiving placebo (25.0%) (P < 0.001) but similar to that in patients receiving adalimumab (68.1%). ACR50 and ACR70 response rates were also superior in both ABT-122 dose groups (36.6-53.4% and 22.5-31.5%, respectively) compared to the placebo group (12.5% and 4.2%, respectively) (P < 0.05). Among eligible patients in the placebo, adalimumab, ABT-122 120 mg every week, and ABT-122 240 mg every week treatment groups, PASI75 responses were achieved in 27.3%, 57.6%, 74.4%, and 77.6% of patients, respectively, whereas PASI90 responses were achieved in 18.2%, 45.5%, 48.8%, and 46.9% of patients, respectively. Frequencies of treatment-emergent adverse events, including infections, were similar across all treatment groups, causing no discontinuations. No serious infections or systemic hypersensitivity reactions were reported with ABT-122. CONCLUSION: Dual neutralization of TNF and IL-17A with ABT-122 had efficacy and safety that was similar to, and not broadly differentiated from, that of adalimumab over a 12-week treatment course in patients with PsA.

Correlation of human cold pressor pain responses with 5-HT(1A) receptor binding in the brain.

We determined whether serotonin 5-HT(1A) receptor availability in the brain is associated with cold pressor pain (CPP) or sympathetic reflex responses. Psychophysical testing was performed in eleven healthy males who had participated in a positron emission tomography study with [carbonyl-(11)C]WAY-100635 ligand for the assessment of 5-HT(1A) receptor binding potential (BP). Psychophysical testing consisted of determining CPP threshold, tolerance, intensity, unpleasantness and CPP threshold modulation by conditioning CPP. Autonomic control was assessed by determining the cutaneous vasoconstriction responses in the finger induced by CPP and Valsalva maneuver. CPP intensity was inversely correlated with 5-HT(1A) BP in multiple cortical and subcortical areas, including the prefrontal and cingulate cortices, insula, amygdala and the dorsal raphe. CPP unpleasantness was not significantly correlated with 5-HT(1A) BP in any of the regions of interest. Increase of CPP threshold by conditioning CPP was directly correlated with 5-HT(1A) BP in the amygdala and medial prefrontal cortex. Vasoconstriction induced by Valsalva but not CPP was directly correlated with 5-HT(1A) BP in the ventral part of the anterior cingulate cortex and the anterior insula. The results suggest that 5-HT(1A) receptors in the brain influence pain and Valsalva-induced sympathetic vasoconstriction reflex. In general, subjects with high availability of 5-HT(1A) receptors have low CPP intensity accompanied by a high capacity for central suppression of pain or a sympathetic vasoconstriction response by a Valsalva maneuver.

Safety, Tolerability, and Pharmacodynamics of ABT-122, a Tumor Necrosis Factor- and Interleukin-17-Targeted Dual Variable Domain Immunoglobulin, in Patients With Rheumatoid Arthritis.

OBJECTIVE: Tumor necrosis factor (TNF) and interleukin-17 (IL-17) independently contribute to the pathophysiology of rheumatoid arthritis (RA). ABT-122 is a novel dual variable domain immunoglobulin that selectively and simultaneously targets human TNF and IL-17A. The aim of treatment with ABT-122 is to evoke a greater clinical response than that achieved by targeting either cytokine alone. This study was undertaken to present the pooled safety, tolerability, and exploratory pharmacodynamics of ABT-122 based on 2 phase I, placebo-controlled, multiple ascending-dose studies in patients with primarily inactive RA. METHODS: Patients (n = 44) receiving stable dosages of methotrexate (2.5-25 mg/week) were randomized to receive subcutaneous placebo, ABT-122 1 mg/kg every other week (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses) and were evaluated through 45 days after the last dose (day 92). Serum samples for the assessment of inflammation markers and chemokines were collected at baseline and on postdose days 3, 5, 8, 15, 29, 57, 64, 78, and 92. RESULTS: No clinically significant findings regarding the safety of ABT-122 were observed. The rates of treatment-emergent adverse events (AEs) were similar in patients receiving ABT-122 and those receiving placebo. Only 1 serious AE (and no systemic hypersensitivity reactions or dose-limiting toxicities) was observed in patients treated with ABT-122. The incidence of infections was similar between patients treated with ABT-122 and those receiving placebo, with no serious infection reported. The levels of CXCL9, CXCL10, CCL23, and soluble E-selectin were significantly decreased following ABT-122 treatment relative to placebo treatment. Although patients had essentially inactive RA, exploratory clinical parameters suggested potential antiinflammatory effects following treatment with ABT-122. CONCLUSION: The results of these phase I studies suggest that dual neutralization of TNF and IL-17 with ABT-122 has characteristics acceptable for further exploration of therapeutic potential in TNF- and IL-17A-driven immune-mediated inflammatory diseases.

Fighter pilots' heart rate, heart rate variation and performance during an instrument flight rules proficiency test.

Increased task demand will increase the pilot mental workload (PMWL). When PMWL is increased, mental overload may occur resulting in degraded performance. During pilots' instrument flight rules (IFR) proficiency test, PMWL is typically not measured. Therefore, little is known about workload during the proficiency test and pilots' potential to cope with higher task demands than those experienced during the test. In this study, fighter pilots' performance and PMWL was measured during a real IFR proficiency test in an F/A-18 simulator. PMWL was measured using heart rate (HR) and heart rate variation (HRV). Performance was rated using Finnish Air Force's official rating scales. Results indicated that HR and HRV differentiate varying task demands in situations where variations in performance are insignificant. It was concluded that during a proficiency test, PMWL should be measured together with the task performance measurement.

Influence of the dopamine D2 receptor knockout on pain-related behavior in the mouse.

We studied the role of the dopamine D2 receptor in physiological regulation of pain-related behavior. The experiments were performed in dopamine D2 receptor knockout mice and in their wild-type controls. Baseline sensitivity to thermal nociception was determined by measuring the response latency in the hot plate at three different stimulus temperatures and by determining the radiant-heat-induced paw withdrawal. Mechanical sensitivity was assessed by determining paw withdrawal responses to stimulation with a calibrated series of monofilaments. Intracolonic capsaicin was used to produce sustained pain-related behavior and referred hypersensitivity to mechanical stimulation. The hot plate response latencies were not significantly different between the dopamine D2 receptor knockout and wild-type animals, although the stimulus temperature-dependent decrease in the response latency was steeper in the wild-type group. The radiant-heat-induced paw withdrawal latency was slightly longer in the knockout animals. The number of capsaicin-induced behavioral responses or the latency to the occurrence of the first capsaicin-induced response was not different between the experimental groups. Dopamine D2 receptor knockout animals were more sensitive to mechanical stimulation of the hindpaws than wild-type animals both in the baseline condition and following development of capsaicin-induced referred hypersensitivity in the hindpaws. The results indicate that dopamine D2 receptors influence baseline nociception in the mouse, although this effect is weak and submodality selective. Additionally, dopamine D2 receptors may contribute to attenuation of referred hypersensitivity caused by sustained nociception.

Association of striatal dopamine D2/D3 receptor binding potential with pain but not tactile sensitivity or placebo analgesia.

Striatal dopamine D2/D3 receptors have been suggested to play a role in pain sensitivity and placebo effect. We studied whether the association of dopamine D2/D3 receptor binding potential (BP) with sensory thresholds is specific to the modality of pain, and whether striatal dopamine D2/D3 receptor BP predicts the magnitude of placebo analgesia. Pain and tactile thresholds, and placebo analgesia were assessed in eight healthy human male subjects who had previously participated in a dopamine D2/D3 receptor positron emission tomography study with [11C]raclopride. The results show that the cutaneous heat pain threshold was inversely correlated with dopamine D2/D3 receptor BP in the right putamen, but responses to tactile stimulation did not correlate with striatal dopamine D2/D3 receptor BP. Placebo-induced elevation of the heat pain threshold did not correlate with striatal dopamine D2/D3 receptor BP. These results suggest that the influence of striatal dopamine D2/D3 receptors on sensory thresholds is selective for the modality of pain. Moreover, striatal dopamine D2/D3 receptor BP appears not to predict individual's analgesic response to placebo.

Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity.

The pain modulatory role of dopamine D2 receptors of the human forebrain was studied by determining the association between dopamine D2 receptor binding potential and the response to experimental pain. Nineteen healthy male volunteers participated in a dopamine D2 receptor positron emission tomography study. The extrastriatal regions of interest studied with [11C]FLB 457 as radioligand (n = 11) were the anterior cingulum, the medial and lateral thalamus, the medial and lateral frontal cortex, and the medial and lateral temporal cortex. The striatal regions of interest studied with [11C]raclopride (n = 8) were the caudate nucleus and the putamen. The latency to the ice water-induced cold pain threshold and tolerance were determined in a separate psychophysical test session. Moreover, the cutaneous heat pain threshold and its elevation by concurrent cold pain in the contralateral hand were determined in each subject. Cold pain threshold was inversely correlated with D2 binding potential in the right putamen and the cold pain tolerance was inversely correlated with D2 binding potential in the right medial temporal cortex. The magnitude of heat pain threshold elevation induced by concurrent cold pain was directly correlated with D2 binding potential in the left putamen. Other correlations of D2 binding potentials in varying brain regions with sensory responses were not significant. A psychophysical control study (n = 10) showed that cold pain responses were identical in the right and left hand. The results indicate that dopamine D2 receptor binding potential in the human forebrain, particularly in the striatum, may be an important parameter in determining the individual cold pain response and the potential for central pain modulation. Accordingly, an individual with only few available D2 receptors in the forebrain is likely to have a high tonic level of pain suppression, combined with a low capacity to recruit more (dopaminergic) central pain inhibition by noxious conditioning stimulation.

The alpha2A-adrenoceptor subtype is not involved in inflammatory hyperalgesia or morphine-induced antinociception.

The purpose of the present study was to investigate the role of the alpha(2A)-adrenoceptor subtype in inflammatory hyperalgesia, and in adrenergic-mu-opioid interactions in acute pain and inflammatory hyperalgesia. Behavioral responses to mechanical and thermal stimuli were studied in alpha(2A)-adrenoceptor knockout mice and their wild-type controls. Thermal nociception was evaluated as paw withdrawal latencies to radiant heat applied to the hindpaws. Mechanical nociception was measured using von Frey monofilament applications to the hindpaws. Mechanical and thermal hyperalgesia, induced with intraplantar carrageenan (1 mg/40 microl) were compared in alpha(2A)-adrenoceptor knockout and wild-type mice. The effects of the systemically administered mu-opioid receptor agonist morphine (1-10 mg/kg) were evaluated on mechanical withdrawal responses under normal and inflammatory conditions in knockout and wild-type mice. Withdrawal responses to radiant heat and von Frey monofilaments were similar in alpha(2A)-adrenoceptor knockout and wild-type mice before and after the carrageenan-induced hindpaw inflammation. Also, the antinociceptive effects of morphine in mechanical nociceptive tests were similar before and after carrageenan-induced hindpaw inflammation. Our observations indicate that alpha(2A)-adrenoceptors are not tonically involved in the modulation of inflammation-induced mechanical and thermal hyperalgesia. In addition, alpha(2A)-adrenoceptors do not appear to play an important role in mu-opioid receptor-mediated antinociception or antihyperalgesia.

Loss of amitriptyline analgesia in alpha 2A-adrenoceptor deficient mice.

Tricyclic antidepressants have analgesic and sedative effects in addition to their antidepressive properties. We tested the acute analgesic and locomotor inhibitory effects of the tricyclic antidepressant amitriptyline and the alpha(2)-adrenoceptor agonist clonidine in wild-type control and in alpha(2A)-adrenoceptor knockout mice in hot-plate and tail-flick tests. Amitriptyline-induced analgesia was lost in alpha(2A)-adrenoceptor knockout mice. The locomotor inhibitory effect of amitriptyline was reduced, but not fully abolished in alpha(2A)-adrenoceptor knockout mice. Similar results were obtained with clonidine. We conclude that alpha(2A)-adrenoceptors appear to have a significant role in amitriptyline-induced acute analgesia in mice, and that alpha(2A)-adrenoceptors also participate in the sedative effects of amitriptyline.

Striatal dopamine D2 receptors in modulation of pain in humans: a review.

We review evidence indicating that the striatum and striatal dopamine D2 receptors are involved in the regulation of pain in humans. Painful stimulation produces an increase in regional cerebral blood flow in the human striatum. Pain is a common symptom in patients with nigrostriatal dopaminergic hypofunction. Positron emission tomography findings show that a low dopamine D2 receptor availability in the striatum of healthy subjects (indicating either a low density of dopamine D2 receptors or a high synaptic concentration of dopamine) is associated with a high cold pain threshold and a low capacity to recruit central pain inhibition by conditioning stimulation. Patients with chronic orofacial pain have higher dopamine D2 receptor availability than their age-matched controls. We propose that the striatal dopamine D2 receptor may be an important target for the diagnosis and treatment of chronic pain.