Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.

Project description:BackgroundPlant extracts with analgesic properties are seldom considered for treatment of acute musculoskeletal pain due to delay in onset of analgesia. Turmeric (Curcuma longa) and boswellia (Boswellia serrata) extracts are well-studied anti-inflammatory compounds gaining in popularity and used as an alternative to conventional treatments for musculoskeletal pain. This study analyzed the analgesic effect of a formulation of turmeric and boswellia extracts in sesame oil (Rhuleave-K, TBF) in reducing exercise-induced acute musculoskeletal pain in healthy participants.MethodsIn this randomized double-blinded placebo-controlled, single-dose, single-day, multicentre study, a total of 232 participants (TBF n = 116; placebo n = 116) having moderate-to-severe exercise-induced acute musculoskeletal pain were randomized in an allocation concealed 1:1 ratio to receive a single dose of 1000 mg of TBF or placebo. The outcome measures were numerical rating scale (NRS), categorical pain relief scale (PRS), onset of analgesia, and short form of McGill questionnaire (SF-MPQ). NRS and PRS were measured from predose to every 30 minutes interval of postdose up to 6 hours at rest, with movement and applying pressure on the affected part. The onset of analgesia was measured from the time of dosage and censored at 6 hours of postdose. The sum of pain intensity difference (SPID6) and total pain relief (TOTPAR6) at 6 hours was, respectively, analyzed from NRS and PRS scores.ResultsTBF showed a significant reduction in pain intensity (SPID6rest) with 97.85% improvement in cumulative responder analysis compared with 2.46% in placebo. The onset of pain relief was fast and highly significant in the TBF group with 99% of participants having a mean perceptible pain relief at 68.5 minutes (95% confidence interval, 59.5-77.4) and 96% of participants having a mean meaningful pain relief at 191.6 minutes (95% confidence interval, 176.7-206.4) compared to the placebo group. Highly significant and continuous improvement in pain relief was observed in the TBF group with 93% of participants having ≥ 50% of maximum TOTPAR6 with a number needed to treat of 1.1 at rest.ConclusionExercise-induced acute musculoskeletal pain can be effectively relieved by TBF (Rhuleave-K) in about 3 hours signifying its strong analgesic activity.

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Pilot, Randomized, Blinded, Placebo-Controlled Trial Investigating the Correlation Between Acid Control and Heartburn Relief with 14 Days of Esomeprazole Treatment.

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