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:BackgroundEpidural analgesia offers greater pain relief compared to systemic opioid-based medications, but its effect on morbidity and mortality is unclear. This review was originally published in 2006 and was updated in 2012 and again in 2016.ObjectivesTo assess the benefits and harms of postoperative epidural analgesia in comparison with postoperative systemic opioid-based analgesia for adults undergoing elective abdominal aortic surgery.Search methodsIn the updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and five trial registers in November 2014, together with reference checking to identify additional studies.Selection criteriaWe included all randomized controlled trials comparing postoperative epidural analgesia and postoperative systemic opioid-based analgesia for adults who underwent elective open abdominal aortic surgery.Data collection and analysisTwo authors independently assessed trial quality and extracted data. We contacted study authors for additional information and data when required. We assessed the level of evidence according to the scale provided by the GRADE working group.Main resultsWe included 15 trials published from 1987 to 2009 with 1498 participants in this updated review. Participants had a mean age between 60.5 and 71.3 years. The percentage of women in the included studies varied from 0% to 28.1%. Adding an epidural to general anaesthesia for people undergoing abdominal aortic repair reduced myocardial infarction (risk ratio (RR) 0.54 (95% confidence interval (CI) 0.30 to 0.97); I(2) statistic = 0%; number needed to treat for one additional beneficial outcome (NNTB) 28 (95% CI 19 to 1423), visual or verbal analogical scale (VAS) scores up to three days after the surgery (mean difference (MD) -1.78 (95% CI -2.32 to -1.25); I(2) statistic = 0% for VAS scores on movement at postoperative day one), time to tracheal extubation (standardized mean difference (SMD) -0.42 (95% CI -0.70 to -0.15); I(2) statistic = 83%; equivalent to a mean reduction of 36 hours), postoperative respiratory failure (RR 0.69 (95% CI 0.56 to 0.85); I(2) statistic = 0%; NNTB 8 (95% CI 6 to 16)), gastrointestinal bleeding (OR 0.20 (95% CI 0.06 to 0.65); I(2) statistic = 0%; NNTB 32 (95% CI 27 to 74)) and time spent in the intensive care unit (SMD -0.23 (95% CI -0.41 to -0.06); I(2) statistic = 0%; equivalent to a mean reduction of six hours). We did not demonstrate a reduction in the mortality rate up to 30 days (RR 1.06 (95% CI 0.60 to 1.86); I(2) statistic = 0%). The level of evidence was low for mortality and time before tracheal extubation; moderate for myocardial infarction, respiratory failure and intensive care unit length of stay; and high for gastrointestinal bleeding and VAS scores.Authors' conclusionsEpidural analgesia provided better pain management, reduced myocardial infarction, time to tracheal extubation, postoperative respiratory failure, gastrointestinal bleeding, and intensive care unit length of stay compared with systemic opioid-based drugs. For mortality, we did not find a difference at 30 days.

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.

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A Nonpeptide Oxytocin Receptor Agonist for a Durable Relief of Inflammatory Pain.

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A Nonpeptide Oxytocin Receptor Agonist for a Durable Relief of Inflammatory Pain.

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