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Sound-including music and noise-can relieve pain in humans, but the underlying neural mechanisms remain unknown. We discovered that analgesic effects of sound depended on a low (5-decibel) signal-to-noise ratio (SNR) relative to ambient noise in mice. Viral tracing, microendoscopic calcium imaging, and multitetrode recordings in freely moving mice showed that low-SNR sounds inhibited glutamatergic inputs from the auditory cortex (ACx) to the thalamic posterior (PO) and ventral posterior (VP) nuclei. Optogenetic or chemogenetic inhibition of the ACx→PO and ACx→VP circuits mimicked the low-SNR sound-induced analgesia in inflamed hindpaws and forepaws, respectively. Artificial activation of these two circuits abolished the sound-induced analgesia. Our study reveals the corticothalamic circuits underlying sound-promoted analgesia by deciphering the role of the auditory system in pain processing.
Learn More >Whilst general anaesthesia is commonly used to undertake spine surgery, the use of neuraxial and peripheral regional anaesthesia techniques for intraoperative and postoperative analgesia is an evolving practice. Variations in practice have meant that it is difficult to know which modalities achieve optimal outcomes for patients undergoing spinal surgery. Our objective was to identify available evidence on the use of regional and neuraxial anaesthesia techniques for adult patients undergoing spinal surgery.
Learn More >Spreading depolarization (SD), usually termed cortical spreading depression has been proposed as the pathophysiological substrate of migraine aura and as an endogenous trigger of headache pain. The links between neurovascular coupling and cortical craniofacial nociceptive activities modulated by SD were assessed by combining local field potential (LFPs) recordings in the primary somatosensory cortex (S1) with functional ultrasound (fUS) imaging of S1 and caudal insular (INS) cortices of anesthetized male rats. A single SD wave triggered in the primary visual cortex elicited an ipsilateral, quadriphasic hemodynamic and electrophysiological response in S1 with an early phase consisting of concomitant increases of relative cerebral blood volume (rCBV) and LFPs. A transient hypoperfusion was then correlated with the beginning of the neuronal silence, followed by a strong increase of rCBV while synaptic activities remained inhibited.LFPs and rCBV recovery period was followed by a progressive increase in S1 and INS baseline activities and facilitation of cortical responses evoked by periorbital cutaneous receptive fields stimulation. Sensitization of cortical ophthalmic fields by SD was bilateral, occurred with precise spatiotemporal profiles and was significantly reduced by pre-treatment with a NMDA antagonist. Combined high-resolution assessing of neurovascular coupling and electrophysiological activities has revealed a useful preclinical tool for deciphering central sensitization mechanisms involved in migraine attacks.A crucial unsolved issue is whether visual aura and migraine headache are parallel or sequential processes. Here we show that a single spreading depolarization (SD) wave triggered from the primary visual cortex is powerful enough to elicit progressive, sustained increases of hemodynamic and sensory responses to percutaneous periorbital noxious stimuli recorded in S1 and Insular ophthalmic fields. Sensitization of cortical ophthalmic fields by SD was bilateral, occurred with precise spatiotemporal profiles and was significantly reduced by pre-treatment with a NMDA antagonist. Combined high-resolution assessing of neurovascular coupling and electrophysiological activities has revealed a useful preclinical tool for deciphering central sensitization mechanisms involved in migraine attacks.
Learn More >Despite a rapid expansion of cannabis use for pain management, how cannabis and prescription opioids are co-used and whether co-use improves analgesia and promotes reduction of opioid use in the daily lives of individuals with chronic pain is poorly understood. Based upon ecological momentary assessment (EMA), the present study examined (1) how pain and use of opioids and/or cannabis in the previous moment is associated with individuals' choice of opioids and/or cannabis in the next moment, (2) the effects of co-use on pain severity and pain relief, and (3) whether daily total opioid consumption differs on days when people only used opioids vs. co-used. Adults with chronic pain (N=46) using both opioids and cannabis who were recruited online completed a 30-day EMA. Elevated pain did not increase the likelihood of co-use in subsequent momentary assessments. Switching from sole use of either opioids and cannabis to co-use was common. Neither co-use nor sole use of either cannabis or opioids were associated with reductions in pain in the next moment. However, participants reported the highest daily perceived pain relief from co-use compared to cannabis and opioid use only. Post-hoc analysis suggested recall bias as a potential source of this discrepant findings between momentary vs. retrospective assessment. Lastly, there was no evidence of an opioid-sparing effect of cannabis in this sample. The present study shows preliminary evidence on cannabis and opioid co-use patterns, as well as the effects of co-use on pain and opoid dose in the real-world setting.
Learn More >We determined the ability of the multi-chemokine receptor (CCR2/CCR5/CCR8) antagonist RAP-103 to modulate pain behaviors in an acute model of surgical pain, with and without an added opioid (morphine), and by itself in a chronic model of Streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN).
Learn More >Anesthetic loss of consciousness induced by chemogenetic excitation of mesopontine effector neurons.
Although general anesthesia is normally induced by systemic dosing, an anesthetic state can be induced in rodents by microinjecting minute quantities of GABAergic agents into the brainstem mesopontine tegmental anesthesia area (MPTA). Correspondingly, lesions to the MPTA render rats relatively insensitive to standard anesthetic doses delivered systemically. Using a chemogenetic approach we have identified and characterized a small subpopulation of neurons restricted to the MPTA which, when excited, render the animal anesthetic by sensorimotor (immobility) and electroencephalographic (EEG) criteria. These "effector-neurons" do not express GABAδ-Rs, the likely target of GABAergic anesthetics. Rather, we report a distinct sub-population of nearby MPTA neurons which do. During anesthetic induction these likely excite the effector-neurons by disinhibition. Within the effector population ~ 70% appear to be glutamatergic, ~30% GABAergic and ~ 40% glycinergic. Most are projection neurons that send ascending or descending axons to distant targets associated with the individual functional components of general anesthesia: atonia, analgesia, amnesia, and loss-of-consciousness.
Learn More >Eptinezumab is an anti-calcitonin gene-related peptide humanized monoclonal antibody approved for the preventive treatment of migraine in adults. The PREVAIL study demonstrated a favorable safety profile with sustained reductions in overall migraine-related burden in patients with chronic migraine (CM). This post hoc analysis aimed to examine item-level changes in the Migraine Disability Assessment (MIDAS) questionnaire over 2 years in participants with CM on eptinezumab treatment.
Learn More >People who have COVID-19 can experience symptoms for months. Studies on long COVID in the population lack representative samples and longitudinal data focusing on new-onset symptoms occurring with COVID while accounting for pre-infection symptoms. We use a sample representing the U.S. community population from the Understanding America Study COVID-19 Survey, which surveyed around 8000 respondents bi-weekly from March 2020 to March 2021. Our final sample includes 308 infected individuals who were interviewed one month before, around the time of, and 12 weeks after infection. About 23% of the sample experienced new-onset symptoms during infection which lasted for more than 12 weeks, and thus can be considered as having long COVID. The most common new-onset persistent symptoms among those included in the study were headache (22%), runny or stuffy nose (19%), abdominal discomfort (18%), fatigue (17%), and diarrhea (13%). Long COVID was more likely among obese individuals (OR = 5.44, 95% CI 2.12-13.96) and those who experienced hair loss (OR = 6.94, 95% CI 1.03-46.92), headache (OR = 3.37, 95% CI 1.18-9.60), and sore throat (OR = 3.56, 95% CI 1.21-10.46) during infection. There was a lack of evidence relating risk to age, gender, race/ethnicity, education, current smoking status, or comorbid chronic conditions. This work provides national estimates of long COVID in a representative sample after accounting for pre-infection symptoms.
Learn More >Immune function and sensitivity to pain are closely related, but the association between early life inflammation and sensory nervous system development is poorly understood-especially in humans. Here, in term-born infants, we measure brain activity and reflex withdrawal activity (using EEG and EMG) and behavioural and physiological activity (using the PIPP-R score) to assess the impact of suspected early-onset neonatal infection on tactile- and noxious-evoked responses. We present evidence that neonatal inflammation (assessed by measuring C-reactive protein levels) is associated with increased spinal cord excitability and evoked brain activity following both tactile and noxious stimulation. There are early indications that this hyperalgesia could be maintained post-inflammation, supporting pre-clinical reports of early-life immune dysfunction influencing pain sensitivity in adults.
Learn More >Buprenorphine is commonly used to control postoperative pain in rodents. Short-acting formulations of buprenorphine (bup-HCl) require frequent handling and restraint of animals for appropriate dosing, which can be stressful and confound research outcomes. Ethiqa XR (bup-ER) is an FDA-indexed extended-release buprenorphine formulation that is an alternative to bup-HCl in mice and rats. In the current study, we first evaluated the pharmacokinetics of bup-ER in male C57BL/6J mice by sampling blood at 10 time points, ranging from 30 min to 72 h after administration ( = 3 mice per time point). Average plasma concentrations fell below therapeutic levels at 48 h after administration. We also evaluated the safety of bup-ER when administered prior to surgery in combination with common anesthetics and the efficacy of bup-ER in mouse laparotomy. Anesthetic safety was studied by measuring respiratory rate, rectal temperature, and recovery time in groups of mice ( = 8) given bup-HCl, bup-ER, or saline in combination with isoflurane or ketamine-xylazine anesthesia. No differences were seen between analgesic treatment groups with either of the general anesthetics. To evaluate efficacy, mice ( = 10) were randomly allocated to receive either bup-ER (3.25 mg/kg) once presurgically, bup-HCl (0.1 mg/kg) presurgically and then every 8 h, or saline once before surgery. Mice underwent a sham laparotomy and were assessed for pain based on changes in weight, cageside ethogram, nesting consolidation test, rearing frequency, and nociception to von Frey testing at 6, 12, 24, 48, and 72 h after surgery. Cageside ethogram, rearing frequency, and von Frey testing showed significant differences between bup-ER-treated mice and saline controls in the early postoperative period. No significant effects between treatment groups were seen in daily weights or nesting consolidation scores. This study demonstrates that bup-ER can be safely administered before surgery and provides analgesia for up to 48 h after administration based on pharmacokinetic and behavioral data.
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