The Role of the Opioid System in Placebo Effects on Pain and Social Rejection

Background:

Loss of close relationships is one of the most aversive life events. An unwanted romantic breakup leads to a 20% risk of developing depression within a month, a dramatic increase in depression risk. The investigators recently identified brain pathways mediating placebo effects on physical heat pain and the social pain associated with an unwanted breakup, including common involvement of dlPFC-PAG pathways and vmPFC. Other recent studies have identified rejection-related opioidergic activity in these circuits that may reflect endogenous regulatory mechanisms. This experiment probes the involvement of the opioid system in placebo effects on social pain, using the opioid antagonist naloxone.

Design:

Extending the investigator's previous design, participants who recently experienced an unwanted breakup will submit pictures of their ex-partners, places associated with strong memories of the partner, and written descriptions of memories that evoke rejection and social pain. Participants will 1) experience rejection-related stimuli and 2) receive painful heat and pressure stimuli in separate runs during fMRI scanning. FMRI scans after Control and Placebo treatment-nasal spray with suggestions of efficacy for emotion and pain-will be performed in a 2-session within-person counterbalanced design. Participants will be randomized into two groups that receive either (1) 4mg naloxone nasal spray or (2) saline in the nasal spray in both sessions, implementing a 2 x 2 (Placebo/Control x Saline/Naloxone) design.

• Placebo Cream with Naloxone (Drug): Participants will be informed that the spray is an effective pain and negative emotion reducing agent.
• Control Cream with Naloxone (Drug): Participants will be informed that the spray is saline.
• Placebo Cream with Saline (Drug): Participants will be informed that the spray is an effective pain and negative emotion reducing agent.
• Control Cream with Saline (Drug): Participants will be informed that the spray is saline.

Primary outcomes

• Intervention effects on pain ratings [Immediately after pain stimuli]: Pain ratings will be given on a 0-100 scale. 0 being "no pain at all" and 100 being "most pain imaginable in the context of this study."
• Intervention effects on negative affect ratings [Immediately after rejection stimuli]: Rejection ratings will be given on a 0-100 scale. 0 being "not rejected at all" and 100 being "very rejected."
• Brain: Pain signature response [Immediately after pain stimuli]: A priori regions of interest response from the brain (fMRI) patterns to the pain.
• Brain: Rejection signature response [Immediately after rejection stimuli]: A priori regions of interest response from the brain (fMRI) patterns to rejection. The investigators will utilize a multivariate brain pattern developed and published in Woo et al., 2014, Nature Communications. This is a rejection-selected pattern of brain activity.
• Skin conductance [Immediately after pain/rejection stimuli]: Skin conductance response (SCR) will be recorded during the task.
• Heart rate [Immediately after pain/rejection stimuli]: Heart rate will be recorded during the task.

Secondary outcomes

• Whole-brain maps of intervention effects [Immediately after pain/rejection stimuli]: Standard resting-state images will be acquired for exploratory analyses. Exploratory brain analysis will include univariate voxel-wise maps comparing participant groups with a threshold of q < 0.05, False Discovery Rate (FDR) corrected.
• Rejection Sensitivity Questionnaire [Within 2 weeks before first fMRI scan]: A measure of sensitivity to actual or perceived rejection with ratings on a 6-point Likert scale ranging from "very unconcerned" - "very concerned." Higher scores indicate more reaction sensitivity.

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

* Adults aged 18-55 years
* No current psychiatric or major neurological diagnosis
* No reported substance abuse within the last six months
* Are capable of performing experimental tasks (e.g., are able to read, able to cooperate with fMRI examination)
* Are fluent or native speakers of English
* No current or recent history of pathological pain or reported neurological disorders.
* Having abstained from alcohol and substance use for 48 hours
* Passed fMRI safety screener
* Experienced a recent unwanted breakup of a romantic relationship

Exclusion Criteria:

* Current presence of pain
* Current or past history of primary psychiatric disorder
* Current or past history of psychoactive substance abuse or dependence
* Dementias
* Movement disorders except familial tremor
* CNS infection
* CNS vasculitis, inflammatory disease or autoimmune disease
* CNS demyelinating disease (e.g. multiple sclerosis)
* Space occupying lesions (mass lesions, tumors)
* Congenital CNS abnormality (e.g. cerebral palsy)
* Seizure disorder
* History of closed head trauma with loss of consciousness
* History of cerebrovascular disease (stroke, TIAs)
* Abnormal MRI (except changes accounted for by technical factors or UBOs)
* Neuroendocrine disorder (e.g., Cushings disease)
* Uncorrected hypothyroidism or hyperthyroidism
* Current or past history of cancer; Recent history (within two years) of myocardial infarction, severe cardiovascular disease, or currently active cardiovascular disease (e.g. angina, cardiomyopathy)
* Uncontrolled hypertension or hypotension
* Chronic pain syndromes
* Chronic fatigue syndromes
* Subjects unable to tolerate the scanning procedures (e.g., claustrophobia)
* Prior treatment within the last month with any of the following: antidepressants, mood stabilizers, glucocorticoids, opiates
* Prior treatment with any of the following: antipsychotics, isoniazid, centrally active antihypertensive drugs (e.g. clonidine, reserpine)
* Metal in body or prior history working with metal fragments (e.g., as a machinist)
* For women, pregnancy
* Any other contraindications for MRI examination (e.g., metallic implants such as pacemakers, surgical aneurysm clips, or known metal fragments embedded in the body)
* Claustrophobia

• Tor D Wager, PhD, Principal investigator, Dartmouth College