A novel investigation of placebo analgesia through social communication in mice.

Background And Aims: In rodents, placebo analgesia is often investigated through direct conditioning of stimuli, but humans can experience placebo analgesia through expectation without experience. In this study, we sought to determine whether placebo analgesia could be elicited through social communication.

Methods: Male and female mice were housed in pairs (designated "Active" and "Bystander") and tested for thermal thresholds on a hot plate (53 °C). Food restriction (1 hr/day) was implemented. The Active mouse was taken to a new cage with food dusted with cocoa (COC) or cinnamon (CINN). The Bystander mice were given regular chow in the home cage. After feeding, the Active mice were given morphine (5 mg/kg, SC) or saline and tested on the hot plate. After 5 pairings of a flavor and treatment (counterbalanced), Active mice were tested following access to a flavored food. Bystander mice were given their first direct exposure to a flavored food and tested on the hot plate. The protocol was repeated with naloxone (10 mg/kg, IP) administered prior to testing. Finally, mice were tested in a two-choice test with both flavored foods available.

Results: Active mice showed a conditioned analgesic response to the morphine-paired flavor that was reduced by naloxone. Bystander mice showed a placebo analgesic response to their cagemate's morphine-paired flavor that was not significantly impacted by naloxone. Bystander mice spent more time in the chamber associated with their cagemate's morphine-paired flavor.

Conclusions: To our knowledge, this is the first investigation of placebo analgesia without direct conditioning, instead relying on social communication between mice. The lack of effect with naloxone pretreatment suggests an opioid-independent effect in the Bystander mice. Placebo analgesia in mice may be possible without direct conditioning to better model the effect of expectation of a novel analgesic in humans.