Background Beginning with experiments in the 1960s, behavioral and pharmacological evidence has indicated that placebo analgesia is mediated by expectations and conditioning. These psychological mechanisms would allow the release of endogenous opioids, cholecistokinins (CCKs), and dopamine (Colloca and Benedetti, 2005). Although tremendous effort has been put into understanding placebo analgesia, many important questions remain to be answered in pursuit of the goal of understanding other mediators involved in its biochemistry. One of the questions to be addressed is whether the oxytocinergic system is involved in placebo analgesic effects. Increasing evidence suggests that two nonapeptides, oxytocin (OXT) and arginine vasopressin (AVP), shape human social behavior in both patients and control subjects (Ebstein, 2009). Given that supportive and empathetic relationships between clinicians and patients induce important clinical placebo effects, it is plausible that OXT is released during positive interactions, while AVP would be predominant in anxiogenic situations. Our goal was to evaluate the effects of OXT and AVP administration on socially-induced placebo analgesia by using painful stimuli in healthy participants. A better understanding of the functional role of OXT and AVP in humans may help to identify a role for these neuropeptides in future clinical practice and allow a better understanding of neurobiology of the placebo analgesia. Much of our knowledge regarding the regulatory function of OXT and AVP of pain and social interactions arises from animal studies using central administration of agonists and antagonists or knockout models. Despite its social, anxiolitic and likely analgesic effects, no attempt has been made to understand whether and how OXT and AVP systems modulate placebo-induced analgesia in humans. Information on research subjects studied A total of 110 participants will be recruited with the goal of obtaining 100 completers. 89 healthy subjects have been enrolled and 88 of them completed the study. The recruitment has been satisfactory for gender (45 M, 44 F) and ethnicity (50 White, 30 Black and 9 Asian participants). We plan to continue the enrollment during the upcoming months/year. So far, a total of 88 completers have been obtained. A non-serious, unexpected adverse event has been reported for one subject withdrawal (see section 8, Unanticipated Problem UP 10/27/2011). Participants are healthy subjects free of current psychopathology and organic central nervous system disorders. The criteria of inclusion and exclusion are rigorously evaluated during the screening process. We include participants who are: 1. Men and Women;2. Aged between 18-55 years;and 3. Able to understand and speak the English language. Moreover, we exclude participants with: 1. Any significant medical or neurological problems (e.g. cardiovascular illness, respiratory illness, neurologic illness, seizures, etc.);2. History of angioedema;3. High or low blood pressure;4. History of fainting;5. A family history of mania, schizophrenia, or other psychoses;6. A history of mania, schizophrenia, or other psychoses;7. Any current Axis I psychiatric disorders;8. Lifetime alcohol/drug dependence;9. Alcohol/drug abuse in the past year;10. Current use of psychotropic medication;11. Impaired hearing;12. Pregnant condition;13. Breast-feeding;and 14 who used of any form of nicotine during the last six months. Subjects are recruited through the NIH list of volunteers and via advertisements in the local media including local newspapers. Equipment/methods This is a single acute treatment study using a between-subjects design. One hundred subjects (males and females) are randomly assigned to 4 Groups (oxytocin, arginine vasopressin, placebo or no-treatment). Randomization is performed by the NIH pharmacy by using a table of random numbers. The four experimental conditions include: 1. OXT (24 IU);2. AVP (40 IU);3. placebo, or 4. no-treatment. Each of the three agents are administered by means of nasal spray over a two-minute period, The fourth no-treatment group (no nasal spray) is necessary to control for spontaneous changes of pain perception. In order to rule out the interactions of exogenous OXT with fluctuations of gonadal steroids over the menstrual cycle, all the sessions are conducted in the mid-luteal phase (women participants). This phase corresponds to a plateau of progesterone levels. It is characterized by constant elevated progesterone and constant low levels of LH and FSH. In period, menstrual-cycle influences are virtually absent (Bos et al., 2010). Procedure After completing the psychological tests for empathy, optimism, and anxiety, participants are tested for tactile (t) and painful (T) thresholds in order to assess a level of moderate pain that is delivered on the dorsum of the non-dominant hand during the two days of the experiment. After the assessment of pain sensitivity, participants receive the drugs via nasal spray. After 45 minutes, when the central nervous levels reach a plateau, participants are asked to re-test for pain and no-pain perception. Participants are informed that a green light displayed on a computer screen will indicate activation of the electrode pasted on their middle finger, which in turn would induce analgesia by virtue of a sub-threshold stimulation. Conversely, a red light indicates that the electrode is not activated, thus they would experience a red light-associated painful stimulus (which serves as control) as previously done (Colloca and Benedetti, 2006 and 2009). Participants receive the same set of information under one of four different pharmacological conditions (OXT, AVP, placebo and no-treatment). They are requested to pay close attention to this phase of treatment presentation. The red or green lights are presented for 5-7 s (randomization of visual cue) and followed by the electric shock. The inter-stimulus interval (ISI) is about 45 s. A total of 18 pairings (18 red+ 18 green) is used. Participants are monitored by recording electrocardiogram, blood pressure, and skin sympathetic response. Psychological questionnaires and saliva samples for cortisol determination are collected at the beginning and end of each session. Before drug administration, participants will be also asked to collect an additional sample of saliva for DNA sequencing through passive drooling. Oragene saliva self-collection kits will be used for collecting and storing saliva necessary for DNA analysis. Oragene saliva self-collection kits are non-invasive and allow us to store saliva samples at room temperature. So far, we have analyzed all the behavioral and neurophysiological responses (skin sympathetic response and heart rate). It is necessary to break the blind to test the main effects of condition, treatment and gender. There is intent to break the blind for the analysis to prepare a progress report for the International Association for Study of Pain (IASP) which partially, funded the current project. We expect to clarify 1. whether OXT is capable of enhancing placebo analgesic responses;2. whether this effect is gender-specific;and 3. whether OXT functional polymorphisms account for these effects. References: Colloca L, Benedetti F. Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci. 2005;6(7):545-52.Colloca L, Benedetti F. Placebo analgesia induced by social observational learning. Pain. 2009;144(1-2):28-34. Ebstein RP, Israel S, Lerer E, Uzefovsky F, Shalev I, Gritsenko I, et al. Arginine vasopressin and oxytocin modulate human social behavior. Ann N Y Acad Sci. 2009 Jun;1167:87-102. Colloca L, Benedetti F: How prior experience shapes placebo analgesia. Pain 2006;124:126-133. Colloca L, Benedetti F. Pain. 2009 Jul;144(1-2):28-34.

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Klinger, Regine; Colloca, Luana; Bingel, Ulrike et al. (2014) Placebo analgesia: clinical applications. Pain 155:1055-8
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