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.

A comparison of the effect of mindfulness and relaxation on responses to acute experimental pain.

BACKGROUND: This study aimed to investigate the efficacy of mindfulness training in comparison with relaxation training on pain, threshold and tolerance during the cold pressor task. METHODS: Undergraduate psychology students (n = 140) were randomly assigned to receive reassuring or threatening information about the cold pressor. Participants were then re-randomized to receive mindfulness or a control intervention: relaxation training. RESULTS: Analyses confirmed that the threat manipulation was effective in increasing worry, fear of harm and expectations of pain, and reducing coping efficacy. Interaction effects revealed that mindfulness was effective in increasing curiosity and reducing decentring under conditions of high threat but not low threat. Other interactions on cognitive variables (attentional bias to pain and self-focus) confirmed that mindfulness and relaxation appeared to exert influences under different conditions (i.e. mindfulness: high threat; and relaxation: low threat). Despite these cognitive effects being discerned under different conditions, there were no differences between mindfulness and relaxation on pain, tolerance or threshold in either threat group. CONCLUSIONS: These results show that a single, brief session of mindfulness based on body scanning is not sufficient to change the way in which individuals approach an experimental pain task in comparison with relaxation, which has previously been shown to be ineffective.

A comparison of the effect of attention training and relaxation on responses to pain.

This study aimed to investigate the efficacy of an attention training technique (ATT) on pain ratings, threshold and tolerance during the cold pressor task. One hundred and three undergraduate students were randomly assigned to receive either threat-alleviating or threat-inducing information about the task. Participants were then re-randomized to receive either ATT or progressive muscle relaxation (PMR). Hence, the present study had a 2 (threat expectancy: high vs. low)x2 (training: ATT vs. PMR) design. Analyses confirmed that the threat manipulation was effective in increasing the harm associated with the task. ATT resulted in a relative reduction in hypervigilance to sensory pain words compared to PMR. ATT was also associated with a lower degree of focus on internal sensations, but not mindfulness or difficulty disengaging from pain words. Results showed that, relative to relaxation training, those receiving ATT reported pain less quickly than those receiving relaxation, although there were no differences between the training groups for tolerance or pain ratings. These results show that ATT changes the cognitive processes of internal/external focus and hypervigilance towards sensory pain words, but not difficulty disengaging or mindfulness. Although ATT changed threshold, the fact that neither pain ratings nor tolerance was affected suggests that a single, brief session of ATT may not be sufficient to affect broader change. Nonetheless, this study shows that ATT can change cognitive processes thought to be associated with heightened perception of pain and that this changes how quickly pain is registered and is therefore worthy of further investigation.

Response phase of the flicker electroretinogram (ERG) is influenced by cone excitation strength.

We measured electroretinogram (ERG) response phases at different cone contrasts in trichromats and dichromats to investigate the dynamics of the long-wavelength-sensitive (L-) and middle-wavelength-sensitive (M-) cone pathways. ERG responses to stimuli, temporally modulated at 30 Hz, were recorded. The stimuli were generated on a computer controlled colour monitor. Thirty-two different combinations of L- and M-cone excitation strength, expressed as cone contrasts, were presented. The short-wavelength-sensitive (S-) cones were not stimulated (S-cone contrast = 0%). The response phase of the fundamental stimulus component was obtained from Fourier analysis. The ERG response phase lags decreased with increasing cone contrast. This was observed in all subjects with a normal appearing fundus. In dichromats and trichromats at low and intermediate contrasts, the phase lags to M-cone isolating conditions were smaller than those to L-cone isolating stimuli. In one dichromat with extreme myopia and cupping of the optic disc, the ERG phase lags increased with increasing cone contrast. The ERG response phase may be potentially useful for detecting retinal abnormalities.

Multiple, but not acute, infusions of cocaine alter the release of prolactin in male rats.

Hypothalamic dopamine tonically inhibits the release of prolactin (PRL) from the anterior pituitary gland. Cocaine, in turn, alters dopaminergic transmission. We compared the effects of acute and repeated injections of cocaine on the release of PRL in male rats to assess whether cocaine could affect dopaminergically mediated hormonal responses. We found that the concentration of PRL in plasma was not affected by single i.v. injections of 1, 3 or 10 mg/kg of cocaine. However, in rats infused repeatedly with 1 mg/kg of cocaine for 5 s every 12 min for 2 h over 10 days, the pre-infusion concentrations of PRL increased in a time-dependent manner whereas cocaine uniformly decreased post-infusion levels of PRL. Repeated administration of cocaine may produce long-term changes in either the tuberoinfundibular dopaminergic neurons or the adenohypophysial dopamine D2-receptors, or both. Changes in the peripheral concentration of PRL after multiple injections of cocaine and during cocaine withdrawal may reflect dopaminergic activity in the hypothalamus. In contrast, single injections of cocaine increased adrenocorticotropin (ACTH) in a dose-dependent manner whereas repeated infusions did not increase peripheral concentrations of ACTH or corticosterone. It seems that repeated injections of cocaine do not result in persistent changes in the hypothalamo-pituitary-adrenal axis.

Drinking induced by injections of angiotensin into forebrain and mid-brain sites of the monkey.

1. Unilateral and bilateral injections of 1.0 mul. solutions of angiotensin II into specific brain sites produced copious drinking of water in the water-replete rhesus monkey (Macaca mulatta).2. Of six brain regions in seven monkeys into which a total of 368 microinjections of angiotensin II were made, three were sensitive to angiotensin II. In decreasing order of sensitivity, they were (i) a rostral zone that included the septum, the anterior hypothalamus and the preoptic region, (ii) a caudal zone consisting of the mesencephalic central grey, and (iii) the lateral and third ventricles near the foramen of Monro. Of the regions tested, those that were relatively inactive included (i) the mid line thalmus, (ii) the mid-brain reticular formation, and (iii) metencephalic points in the cerebellum, the 4th ventricle and the dorsal aspect of the pons.3. Bilateral microinjections of angiotensin II into the sensitive regions in doses as low as 0.75-6 ng were dipsogenic and, with increasing doses, drinking occurred in a dose-dependent fashion up to 500 ng, after which the amount drunk levelled off or was reduced. The dose-response curve for unilateral microinjections began at 12.5 ng, and at doses higher than 50 ng unilateral and bilateral microinjections were equipotent.4. The onset of drinking (without eating) averaged 2.1-3.2 min following the end of microinjections for all sensitive tissue sites. Injections into the ventricles produced significantly longer drinking latencies.5. Angiotensin I elicited drinking in amounts comparable to angiotensin II at a dose of 100 ng whereas analogues of angiotensin II were weak dipsogens. Of the three analogues tested, Phe(4), Tyr(8)-angiotensin II was the most potent dipsogen, followed by Ile(8)-angiotensin II. The 1-7 heptapeptide, des-Phe(8)-angiotensin II was an ineffective dipsogen. Carbachol microinjected into the most sensitive angiotensin drinking sites had no dipsogenic action in the water-replete monkey.6. Tachyphylaxis to angiotensin II was demonstrated as a reduction in mean water intake of 55 and 74 per cent on the second and third microinjections, respectively. This reduction appeared to be due to dilutional inhibition or signals from the amount of water ingested on the first microinjection of angiotensin II.7. Monkeys drank an amount equal to a normal daily intake following two to three microinjections of angiotensin II in doses of 100-250 ng into sensitive regions. This extra water load caused no reductions in normal daily water intake either for the remainder of the experimental day or 24 hr later.8. Pre-treatments with microinjections of an angiotensin-converting enzyme inhibitor, SQ 20,881, did not reduce the dipsogenic action of angiotensin I, suggesting that this and perhaps other peptide precursors act directly on receptor mechanisms to produce drinking. Attempts to change the polydipsic effects of angiotensin II were unsuccessful with pre-treatments of intracranial microinjections of either haloperidol, Ile(8)-angiotensin II or carbachol.9. Microinjections of angiotensin II dissolved in hypertonic saline solutions had no influence on water intake when compared with the same dose dissolved in distilled water or isotonic saline.10. Yawning was the only other response that appeared to be related directly to intracranial injections of angiotensin II. In some instances, a hyperactive state of the animal followed intraventricular injections of angiotensin II. In other instances, intracranial microinjections of angiotensin II were followed by quietude or e.e.g. and behavioural signs of light sleep.11. This work further confirms the findings of previous research which showed that angiotensin II is the most potent dipsogen in all species tested to date. This endogenous peptide appears to participate in natural thirst by acting on central mechanisms of extracellular thirst.

Brain lesions in an infant rhesus monkey treated with monsodium glutamate.

In an infant rhesus monkey brain damage resulted from subcutaneously administered monosodium glutamate. Although a relatively high dose of monosodium glutamate was used, the infant was asymptomatic for a 3-hour observation period during which time hypothalamic neurons were undergoing a process of acute cell death. With the electron microscope it was observed that dendrites and cell bodies of neurons are the tissue components primarily affected in brain damage induced by monosodium glutamate.

Temperature in the monkey: transmitter factors released from the brain during thermoregulation.

When perfusate is collected from the anterior hypothalamus of a cooled donor monkey and is transfused to a corresponding hypothalamic site in a normal monkey, fever occurs in this recipient. Conversely, perfusate from a heated donor monkey lowers the recipient monkey's temperature when the same hypothalamic transfusion procedure is followed. These experiments provide direct evidence of a neurochemical "coding" within the specific anatomical region of the brain historically implicated in the control of body temperature.