Pre-Exposure, But Not Overshadowing, Inhibits Nocebo Hyperalgesia.

Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies - overshadowing (Experiment 1) and pre-exposure (Experiment 2) - could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode 'activated', which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings. PERSPECTIVE: Nocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.

Early experience and reinforcer quality in delayed flavour-food learning in the rat.

The ability of hungry rats to associate flavours with the consequences of ingesting glucose solutions was studied in three experiments. Experiment 1 used a procedure in which on some days one flavour, e.g. cinnamon, was presented and followed after 20 min by 20% glucose, while on other days a second flavour, e.g. wintergreen, was presented, but not followed by any event. During this training, subjects who received quinine-tainted glucose increased their consumption of the predictive flavour relative to groups given no quinine, but quinine tainting did not affect conditioned preference for the predictive flavour in choice tests. With the aim of discovering whether prior experience of a variety of foods improves ability to learn new flavour-calorie associations, Experiment 2 and used a similar procedure to compare subjects raised on a varied diet ("supermarket" rats) with controls previously given only chow. Contrary to expectation, the supermarket rats showed some impairment both on this delay task and, in Experiment 3, on one using a "mixtures" procedure. This involved presenting a mixture of one cue flavour with glucose-quinine on some days and a mixture of a second cue with an equally palatable saccharin solution on other days. Acquisition was particularly rapid in control subjects, reaching asymptote after only two flavour-glucose pairings. It was concluded that neither a decrease in palatability, as in Experiment 1, nor prior experience with a range of foods, as in Experiments 2 and 3, improve a rat's ability to associate a new flavour with calories.