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.

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