Effects of Intranasal Oxytocin Administration on Social Influence Effects on Pain

Background:

The placebo literature suggests that both conceptual (i.e. socially instructed beliefs) and
associative learning processes are critical for the genesis of placebo effects. Several
studies have performed placebo 'conditioning' (associating a sham treatment with reduced pain
through repeated experience) but interfered with conceptual processing by informing subjects
that the intensity of the stimulus was being lowered. This manipulation prevented the
attribution of pain reductions to the placebo treatment during the learning process. These
studies showed no conditioned analgesia. However, when the same 'conditioning' was performed
without the verbal explanation for why the treatment seemed to work, robust placebo effects
were created. Conceptual processes appear to be critical. Conversely, several studies have
manipulated conceptual expectations alone, by manipulating verbal instructions, and have
found markedly reduced or absent placebo analgesia on both pain report and brain
event-related potentials. Learning by experience also seems to be critical.

These studies separately have led to the conclusions that 'expectancy' and 'conditioning' are
each critical processes, and debates have focused on which one is the driver of placebo
effects. The investigators propose another view: Both processes are critical, and they
interact. Experience drives changes in value learning systems, but in any type of value
learning, there is a 'credit assignment' problem, and the brain must decide which cue-outcome
associations to update as a result of experience: Is the pain reduced because the treatment
was effective or because the cause of pain changed? Conceptual processes fill the gap,
drawing on explicit memory and generalization from similar past experiences to solve the
credit assignment problem, creating analgesia if experienced relief is attributed to the
treatment. This view is compatible with older information based theories of conditioning and
new evidence that rats and humans alike maintain expectancies about specific outcomes and
mental models of contingencies that are distinct from associative learning. In spite of
dozens of published studies demonstrating effective placebo analgesia with the established
paradigm the investigators use, the precise nature of the learning that occurs is unknown,
because placebo analgesia has not typically been studied from a learning-systems perspective.
The aim of the present study is to assess the influence of social information and associative
learning on placebo analgesia.

In addition, interactions between neurochemical systems and placebo analgesia have hardly
been explored, and this proposal represents a significant effort in that regard. For example,
oxytocin interacts synergistically with opioids in the PAG (periaqueductal gray) (and CCK
(Cholecystokinin)) to relieve pain, and in a separate literature reliably increases trust and
reduces anxiety in interpersonal situations. In spite of the fact that oxytocin has been
proposed as central to the placebo effect and can be administered to humans with no known
subjective effects or side effects, its role in placebo analgesia has not been explored
extensively. The experiment proposed here will clarify the roles of the oxytocin system and
its contributions to social facilitation of analgesia, and will be instrumental in developing
a systems-based model of placebo effects.

Experimental Design:

Participants will perform two tasks in each experimental session. First, they will perform a
social-influence and learning task to investigate the effects of oxytocin on social
instruction effects and learning on pain. Second, they will perform a social-support during
pain, to test the effects of oxytocin on the pain-alleviating effects of social support
during pain.

Inclusion Criteria:

- Subject is a volunteer between 18 and 40 years of age.

- If female, subject is non-lactating, not pregnant, and using a reliable contraception
method

- Subject is able to read and speak English.

- Subject is able and willing to provide written informed consent.

- Subject is able to understand and follow the instructions of the investigator and
understand all screening questionnaires.

- Subject is in good health.

- For participants to be eligible for all tasks of the study, the participant must have
a romantic partner and be willing to bring the partner to the study session.

Exclusion Criteria:

- Tests positive on the 14 panel poly-substance urine drug screen for illicit substances
(e.g., marijuana (THC), cocaine (COC), phencyclidine (PCP), amphetamine (AMP), ecstasy
(MDMA), methamphetamine (Mamp), opiates (OPI), oxycodone (OXY), methadone (MTD),
barbiturates (BAR), benzodiazepines (BZO), buprenorphine (BUP), tricyclic
antidepressants (TCA), propoxyphene (PPX))

- Chronic Pain

- Do not have the ability to tolerate heat pain applied to the forearm

- Have temporary abnormal levels of pain

- Have score of > 19 using the Center for Disease and Epidemiology Depression Scale

- Current treatment (e.g., medications or therapy) for psychiatric disorders, including
mood, anxiety, substance abuse, Attention-deficit/hyperactivity disorder (ADHD),
psychosis; Neurological disorders (e.g., taking dopamine agonists for Parkinson's);
Cardiovascular disease or medication (e.g., taking ACE (angiotensin-converting-enzyme)
inhibitors for cardiac remodeling)

- Frequent smoking (> 5 cigarettes / day); frequent alcohol use (>14 drinks / week);
frequent migraines (> 5 / month on average) or a history of neurologic disease or
neuropathic pain.

- Any allergy to Oxytocin