Expectations about the magnitude of impending pain exert a substantial effect on subsequent perception. However, the neural mechanisms that underlie the predictive processes that modulate pain are poorly understood. In a combined behavioral and high-density electrophysiological study we measured anticipatory neural responses to heat stimuli to determine how predictions of pain intensity, and certainty about those predictions, modulate brain activity and subjective pain ratings. Prior to receiving randomized laser heat stimuli at different intensities (low, medium or high) subjects (n=15) viewed cues that either accurately informed them of forthcoming intensity (certain expectation) or not (uncertain expectation). Pain ratings were biased towards prior expectations of either high or low intensity. Anticipatory neural responses increased with expectations of painful vs. non-painful heat intensity, suggesting the presence of neural responses that represent predicted heat stimulus intensity. These anticipatory responses also correlated with the amplitude of the Laser-Evoked Potential (LEP) response to painful stimuli when the intensity was predictable. Source analysis (LORETA) revealed that uncertainty about expected heat intensity involves an anticipatory cortical network commonly associated with attention (left dorsolateral prefrontal, posterior cingulate and bilateral inferior parietal cortices). Relative certainty, however, involves cortical areas previously associated with semantic and prospective memory (left inferior frontal and inferior temporal cortex, and right anterior prefrontal cortex). This suggests that biasing of pain reports and LEPs by expectation involves temporally precise activity in specific cortical networks.

Cutaneous inflammation induced by ultraviolet (UV) irradiation in the UV-B range has received significant recent interest as a translational inflammatory pain model. Changes in thermal and mechanical sensitivities in the area of primary hyperalgesia are well documented in both the rat and human UV-B models, but the occurrence of secondary mechanical hyperalgesia is controversial. We investigated the occurrence of secondary mechanical hyperalgesia in the rat UV-B model. Additionally, we investigated whether secondary hyperalgesia was enhanced by heat rekindling of UV-B-irradiated skin as a new rat inflammatory model of sensitisation with an enhanced central contribution. UV-B irradiation (1000 mJ/cm(2)) induced significant secondary mechanical hyperalgesia and allodynia that peaked at 48 h. Heat rekindling (45 °C stimulus for 5 min) of UV-B-irradiated skin at 24h further enhanced and prolonged this secondary mechanical hyperalgesia and allodynia, with a peak at 72 h. Heat rekindling also induced a significant mechanical hyperalgesia and allodynia on the contralateral hind paw, further suggesting the contribution of central sensitisation. Our data provide strong evidence for a central contribution in both the rat UV-B pain model and an enhanced contribution in the new model combining UV-B irradiation with heat rekindling. We also elucidate potential differences in the methods used by ourselves and others to obtain mechanical withdrawal thresholds in rats, which may explain the lack of secondary hyperalgesia in the rat UV-B model.

IntroductionAlthough there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain.ObjectivesHere, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers.MethodsFifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session.ResultsOur investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood.ConclusionAs far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes.