Sensory and Opioid Mechanisms of Affective Touch

Objective: Our recent pilot study found evidence suggesting that blocking endogenous opioid
release increases the pleasantness associated with having the skin stroked. Deep pressure
touch (observed in hugs and massage) also typically conveys a sense of pleasantness. This
increased pleasantness contrasts with evidence that blocking endogenous opioid release
increases pain. The current study will examine the role of endogenous opioids in the
pleasantness of light skin stroking and deep pressure touch, and contrast it with their role
in the unpleasantness of a painful heat stimulus. Further, it will examine the neural basis
of observed perceptual changes, using fMRI. This study constitutes the first study of the K99
phase of a K99/R00 grant application recently submitted to NCCIH by Dr. Laura Case.

Study Population: 30 healthy participants will be enrolled in the study.

Design: Participants will receive intravenous saline or intravenous naloxone on separate days
to investigate the effect of mu-opioid antagonism on the intensity and pleasantness of
superficial and deep affective touch and the intensity and unpleasantness of cutaneous heat
pain. Using a double-blind cross-over design, functional Magnetic Resonance Imaging (fMRI)
will be conducted during sensory testing before and after the infusion of each drug to
examine the neural mediation of opioid effects on touch perception. Ratings of mood, anxiety,
pain intensity, pleasantness/unpleasantness, wanting and liking will also be collected
throughout the study session.

Outcome measures: We will compare subjective ratings (mood, calmness, anxiety, pleasantness,
wanting, liking, pain intensity and unpleasantness) during naloxone and saline to: 1)
Determine whether naloxone increases the pleasantness and/or intensity of affective touch
(light brush and deep compression); 2) Determine whether naloxone increases the
unpleasantness and/or intensity of cutaneous heat pain; 3) Determine the role of mood or
anxiety changes in mediating the effect of endogenous opioids on these perceptual measures;
3) Determine changes in the brain activation related to these effects.

- INCLUSION CRITERIA:

All subjects must be:

- Between 18 and 50 years old.

- Right-handed (on Edinburgh Handedness Inventory).

- Fluent in English.

- Able to provide written informed consent.

EXCLUSION CRITERIA:

Overall exclusion criteria for the study:

- Unable to comply with study procedures (or does not rate stimuli as tolerable) or
unable to schedule visits promptly (including inability to schedule the second session
within approximately 14 days of the first session)

- Pregnancy or breastfeeding.

- Use of recreational drugs in the past month (e.g., marijuana, MDMA [ ecstasy or molly
], LSD, cocaine, methamphetamine, heroin, prescription and/or opioids).

- Congenital lower limb deficiency or amputation.

- Peripheral neuropathy, dermatological condition such as scars or burns, or has had a
tattoo in the testing region within the previous four weeks that might influence
cutaneous sensibility.

- Women who consume more than 7 alcoholic beverages per week, and men who consume more
than 14 drinks per week.

- Current chronic pain condition or has had chronic pain in the past year (painful
condition lasting more than six months), including ongoing treatment with medications
for neuropathic pain (e.g. gabapentin, tricyclic antidepressants, pregabalin,
tramadol)

- Major medical condition, such as kidney, liver, cardiovascular (including blood clots,
hypertension, preexisting cardiac arrhythmia), autonomic, pulmonary, or neurological
problems (e.g., seizure disorder ) or a chronic systemic disease (e.g., diabetes).

- Current diagnosis or pharmacological treatment of psychiatric disorders such as major
depression, major anxiety-related problems, post-traumatic stress syndrome, bipolar
disorder, psychosis, attention-deficit/hyperactivity disorder or current or lifetime
alcohol or substance abuse disorders (as identified in study #16-AT-0077)

- Participant has metal in his/her body which would make having an MRI scan unsafe, such
as pacemakers, medication pumps, aneurysm clips, metallic prostheses (including metal
pins and rods, heart valves or cochlear implants), shrapnel fragments, permanent eye
liner or small metal fragments in the eye that welders and other metal workers may
have.

- Participant is uncomfortable in small closed spaces (has claustrophobia) so that
he/she would feel uncomfortable in the MRI machine or cannot lie comfortably flat on
his/her back for up to 75 minutes in the MRI scanner.

- Participants weighs more than 550 lbs.

- Participant has taken any pain medication other than an over-the-counter NSAIDs or
acetaminophen within the last month or for more than one month on a continual basis
within last six months.

- Previous participation in 13-AT-0143 (related study).

- NIH employees who are subordinates, relatives, or co-workers of the investigators, or
NCCIH DIR employees.

- Participants using medications that play into opioid pathways (e.g. loperamide or
dextromethorphan), that could potentially interact with naloxone (naltrexone,
methylnaltrexone, droperidol, fenfluramine and clonidine)

- Participant using any herbal supplements (such as yohimbine) due to risk of unknown
dangerous interaction as there is no data for herbal preparations and naloxone.

- Participant has allergies to naloxone or similar drugs.

EXCLUSION CRITERIA FOR INIDIVIDUAL STUDY SESSION:

- Has consumed alcohol within 24 hours, shows signs of alcohol withdrawal syndrome, or
has behavioral signs of intoxication will be excluded immediately and not have the
possibility to reschedule their session.

- Used topical pain-relieving creams in the testing area (e.g. methylsalicylate,
capsaicin) within 24 hours of testing or used non-steroidal anti-inflammatory drugs
(NSAIDS, e.g. aspirin, ibuprofen), acetaminophen, or naproxen within 3 days of
testing*.

- To be determined during the pre-session screening. Participants who cannot
refrain from these activities may have their session rescheduled up to two times.
If the participant is found non-compliant during the second rescheduled
appointment, he or she will be excluded from the study.