Placebo effects held an ambivalent place in health care for at least two centuries. On the one hand, placebos are traditionally used as controls in clinical trials to correct for biases and the placebo response is viewed as an effect to be factored out in order to isolate and accurately measure the effects of the treatment. On the other hand, there is scientific evidence that placebo effects represent fascinating psychoneurobiological events involving the contribution of distinct central nervous as well as peripheral physiological mechanisms that influence pain perception and clinical pain symptoms and substantially modulate the response to pain therapeutics. Therefore, placebo effects have shifted from being a challenge for clinical trials to a resource to trigger the reduction of pain based on endogenous mechanisms that can be activated in the brain to promote hypolagesia, self-healing, and well-being. This is relevant in acute pain settings given that chronic opioid users die within approximately 2.5 years of being prescribed their first opioid medication to treat acute pain.

The overall hypothesis is that observational learning influences neural pain modulation and cognition systems, including processes associated with mentalizing (the ability to cognitively understand mental states of others), empathy (the ability to share an emotional experience), and expectancy (the anticipation of a benefit). The objective is to determine the brain mechanisms of observationally-induced analgesia using brain mapping approaches that target changes in blood oxygenation and oscillatory activity in the brain, thus enabling investigators to draw inferences about the localization and extent of neurobiological activation underlying hypoalgesia driven by observation. Therefore, the investigators designed innovative experiments using pharmacological fMRI, EEG, and combined EEG-fMRI measurements.

Analgesic effects can also occur without formal conditioning and direct prior experience because crucial information necessary to build up expectations of analgesia can be acquired through observation of a therapeutic benefit in others. Placebo analgesic effects following the observation of a benefit in another person are similar in magnitude to those induced by directly experiencing an analgesic benefit. These observations emphasize that contextual cues substantially modulate the individual placebo analgesic effects.

In this project, the investigators propose a compelling research agenda to explore the neural mechanisms of hypoalgesia driven by observation as a foundation for future development of novel nonpharmacological pain therapies using pharmacological functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and combined EEG/fMRI. It builds on a decade of experience in placebo research in PI Colloca's lab and with University of Maryland collaborators experienced in brain mapping and pain research. In Aim 1, the investigators will determine the role of endogenous opioids on the neural mechanisms of observationally-induced hypoalgesia by using the opioid antagonist naloxone in a functional Magnetic Resonance Imaging (fMRI) setting. In Aim 2, the investigators will identify the impact of empathy by exploring how being in the immersive environment can enhance observationally-induced analgesia. In Aim 3, the investigators will leverage the EEG/fMRI to determine the neural EEG/fMRI transient changes that could co-occur when socially-induced expectations are violated.

Inclusion Criteria:

• Age (18-65 years old)
• English speaker (written and spoken)

Exclusion Criteria:

• Cardiovascular, neurological diseases, pulmonary abnormalities, kidney disease, liver disease, degenerative neuromuscular disease, or history of cancer within past 3 years
• Any history of chronic pain disorder or currently in pain
• Severe psychiatric condition (e.g. schizophrenia, bipolar disorders, mania, autism) and /or psychiatric condition leading to treatment and/or hospitalization within the last 3 years.
• Personal history of mania, schizophrenia, or other psychoses
• Nasal Polyps
• Chronic intranasal drug use ( e.g., intranasal decongestants; antihistamines)
• Lifetime alcohol/drug dependence, or alcohol/drug abuse in past 3 months
• Use of antidepressants, ADHD medication, non-over-the-counter painkillers, methadone, benzodiazepines, barbiturates, and/or narcotics during the past 3 months
• Pregnancy or breast feeding
• Color-blindness
• Impaired, uncorrected hearing
• Left handed
• Allergies or sensitivities to creams, lotions, or food coloring
• Any non-organic implant or any non-removable metal device (e.g., pacemaker, cochlear implants, stents, surgical clips, non-removable piercings)
• Any prior eye injury or the potential of a foreign body in the eye (e.g., worked in metal fields)
• Persistent functional impairment due to a head trauma
• Fear of closed spaces
• Any other contraindications for MRI (e.g., large tattoos on head and neck)
• Previously participated in other "Pain Perception in the Brain" Studies in Colloca lab Failed drug test (testing for opiates, cocaine, methamphetamines, amphetamines, and THC)

At this time, there is neither intent nor plan to share IPD.

The UM Pharmacy will assign de-identified study IDs to participants and provide the study drug (Naloxone or Saline) so that participants, the person conducting the experiment, and the investigator will be blind to the participant's group.