Marsili Syndrome as a Gateway to Novel Analgesic Targets

Condition(s) studied

Investigational drug(s) / intervention(s)

Histamine: To deliver histamine, standard allergy skin prick test (SPT) lancets are applied

Cowhage (Mucuna Pruriens): The spicules will be manually inserted. Approximately 30-35 spicules are gently rubbed into a 1 cm diameter skin area on the forearm

Capsaicin 8% Patch: Capsaicin patches (2x2 cm, dosage form: transdermal patch 8%) will be applied on the selected area. The patch will be left in place for 30 minutes after which it will be removed.

Knee Injections of hypertonic saline: Experimental knee pain will be induced with a 0.25-0.30 mL bolus injection of 5% hypertonic saline, which will be injected into the dominant Infrapatellar Fat Pad (IFP)

Cold Pressure Test: Participants will be asked to place their hand in the cold-water tank (temperature around 5°C) and to keep it for as long as they can tolerate it.

Computerized Conditioned Pain Modulation (CPM): CPM will be assessed using a double-cuff.

Study summary

Congenital insensitivity to pain (CIP) comprises a group of rare genetic disorders caused by mutations in genes essential for pain sensing in humans. Among these, Marsili syndrome is caused by a dominant point mutation in the transcription factor ZFHX2, and it is characterized by markedly reduced sensitivity to noxious heat, mechanical injury, while other functions remain intact. this project aims to establish the first integrated, system-level characterization of Marsili syndrome by combining human sensory phenotyping with neurophysiological and molecular analyses. The study will be conducted in two sessions of approximately 4 hours each, 24 hours apart from each other

Eligibility

Primary outcome measure(s)

• Measuring pain by computerized Visual Analog Scale Scoring — Day 1
  We will ask the subjects to rate the sensation of pain on a scale from 0 to100, where 0 represents no pain and 100 represent the worst imaginable pain.
• Measuring pain by computerized Visual Analog Scale Scoring — Day 2
  We will ask the subjects to rate the sensation of pain on a scale from 0 to100, where 0 represents no pain and 100 represent the worst imaginable pain.
• Measuring Itch by computerized Visual Analog Scale Scoring — Day 1
  We will ask the subjects to rate the sensation of itch on a scale from 0 to100, where 0 represents no itch and 100 represent the worst imaginable itch.
• Measuring Itch by computerized Visual Analog Scale Scoring — Day 2
  We will ask the subjects to rate the sensation of itch on a scale from 0 to100, where 0 represents no itch and 100 represent the worst imaginable itch.
• Alloknesis — Day 1
  Measured using a standardized sensory brush exerting a force of 200 to 400 mN.
• Alloknesis — Day 2
  Measured using a standardized sensory brush exerting a force of 200 to 400 mN.
• Mechanically evoked itch (MEI) — Day 1
  MEI is measured by using mildly pruritic, non-painful von Frey nylon filaments of a predetermined intensity (generally 5-30 miliNewton of force).
• Mechanically evoked itch (MEI) — Day 2
  MEI is measured by using mildly pruritic, non-painful von Frey nylon filaments of a predetermined intensity (generally 5-30 miliNewton of force).
• Mechanical Pain Thresholds (MPT) — Day 1
  This test is conducted using a pinprick set. The set consists of 7 needles each with a diameter of 0.6 mm and different force applications: 8, 16, 32, 64, 128, 256, and 512 mN.
• Mechanical Pain Thresholds (MPT) — Day 2
  This test is conducted using a pinprick set. The set consists of 7 needles each with a diameter of 0.6 mm and different force applications: 8, 16, 32, 64, 128, 256, and 512 mN.
• Mechanical Pain Sensitivity (MPS) — Day 2
  This test is conducted with the same pinprick set used to test the MPT.
• Mechanical Pain Sensitivity (MPS) — Day 1
  This test is conducted with the same pinprick set used to test the MPT.
• Pressure Pain Threshold — Day 1
  Pressure pain threshold (PPT) is obtained using a manual pressure algometer
• Pressure Pain Threshold — Day 2
  Pressure pain threshold (PPT) is obtained using a manual pressure algometer
• Mechanical Suprathreshold Pain Stimulation — Day 2
  Once PPT has been determined, stimuli of 130% of the PPT will be delivered to the limb or shoulder to create a sensation of subjective mild/moderate pain
• Computerized Cuff Pressure Algometer (CPA) — Day 1
  A computer-controlled cuff pressure algometer works by inflating a cuff/tourniquet, which is similar in design to those used for measuring blood pressure
• Spatial and Temporal Summation of Pain — Day 1
  Spatial and temporal summation of pain will be assessed with the use of the computerized cuff pressure algometer
• Cold Detection Thresholds (CDT) — Day 1
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Cold Detection Thresholds (CDT) — Day 2
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Warm Detection Thresholds (WDT) — Day 1
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Warm Detection Thresholds (WDT) — Day 2
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Cold Pain Thresholds (CPT) — Day 1
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Cold Pain Thresholds (CPT) — Day 2
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Heat Pain Thresholds (HPT) — Day 1
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Heat Pain Thresholds (HPT) — Day 2
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Pain to Supra-threshold Heat Stimuli (STHS) — Day 1
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• Pain to Supra-threshold Heat Stimuli (STHS) — Day 2
  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device
• EEG recording — Day 1
  The EEG signal will be acquired constantly through 64 electrodes placed on the scalp according to the international 10-20 system with a standard EEG cap
• Measuring cortical responses to magnetic stimulation — Day 1
  Transcranial magnetic stimulation (TMS) will be used to evoke cortical responses (TMSevoked potentials - TEPs) in the left and right motor cortex with a figure-eight-shaped cone coil (200 pulses for each target).

Trial sites (1)

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