Abstract:Maintaining effective analgesia during invasive procedures performed under general anesthesia is important for minimizing postoperative complications and ensuring satisfactory patient wellbeing and recovery. While patients under deep sedation may demonstrate an apparent lack of response
to noxious stimulation, areas of the brain related to pain perception may still be activated. Thus, these patients may still experience pain during invasive procedures. The current study used anesthetized or sedated cynomolgus… Show more
“… 53 In a previous study in naïve macaques, significant activation of contralateral Ins/SII during noxious cutaneous pressure stimulation of the foot was observed during infusion of anesthetic doses of propofol. 40 In the current study, in naïve macaques, no significant brain activation was observed up to 30 ml rectal distention and this could have been in part due to propofol anesthesia. More likely, however, is that the rectal distention volumes used in the current study were not noxious.…”
Section: Discussioncontrasting
confidence: 43%
“…Macaques were sedated during each scan by infusion of a non‐analgesic dose of propofol (0.2 mg/kg/h; Maruishi Pharmaceutical). 38 , 39 , 40 Heads were fixed with an MR compatible acrylic head holder (Matsui Co.). During the scan, macaques were kept warm with blankets and heating pads.…”
Greater understanding of the mechanism that mediates visceral pain and hypersensitivity associated with irritable bowel syndrome (IBS) would facilitate the development of effective therapeutics to manage these symptoms. An objective marker associated with the underlying mechanisms of visceral pain and hypersensitivity could be used to guide therapeutic development. The current study examined brain activation evoked by rectal distention with functional magnetic resonance imaging (fMRI) in a cynomolgus macaque model of visceral hypersensitivity. Male, cynomolgus macaques underwent five four‐week treatments of dextran sodium sulfate (DSS)‐distilled water (DW), which induced mild–moderate colitis with remission during each treatment cycle. Balloon rectal distention (RD) was performed under anesthesia 14 weeks after the final DSS‐DW treatment. Colonoscopy confirmed the absence of colitis prior to the start of RD. In naïve, untreated macaques, 10, 20 and 30 ml RD did not evoke brain activation. However, insular cortex/somatosensory II cortex and cerebellum were significantly activated in DSS‐treated macaques at 20 and 30 ml rectal distention. Intra‐rectal pressure after DSS treatment was not significantly different from that of naïve, untreated macaques, indicating lack of alteration of rectal functioning following DSS‐treatment. Treatment with 5‐HT3 receptor antagonist alosetron (p.o.) reduced distension‐evoked brain activation and decreased intra‐rectal pressure. The current findings demonstrated activation of brain regions to RD following DSS treatments which was not present in naïve macaques, suggesting visceral hypersensitivity. Brain activation in turn was reduced by alosetron, which could underlie the analgesic effect alosetron in IBS patients.
“… 53 In a previous study in naïve macaques, significant activation of contralateral Ins/SII during noxious cutaneous pressure stimulation of the foot was observed during infusion of anesthetic doses of propofol. 40 In the current study, in naïve macaques, no significant brain activation was observed up to 30 ml rectal distention and this could have been in part due to propofol anesthesia. More likely, however, is that the rectal distention volumes used in the current study were not noxious.…”
Section: Discussioncontrasting
confidence: 43%
“…Macaques were sedated during each scan by infusion of a non‐analgesic dose of propofol (0.2 mg/kg/h; Maruishi Pharmaceutical). 38 , 39 , 40 Heads were fixed with an MR compatible acrylic head holder (Matsui Co.). During the scan, macaques were kept warm with blankets and heating pads.…”
Greater understanding of the mechanism that mediates visceral pain and hypersensitivity associated with irritable bowel syndrome (IBS) would facilitate the development of effective therapeutics to manage these symptoms. An objective marker associated with the underlying mechanisms of visceral pain and hypersensitivity could be used to guide therapeutic development. The current study examined brain activation evoked by rectal distention with functional magnetic resonance imaging (fMRI) in a cynomolgus macaque model of visceral hypersensitivity. Male, cynomolgus macaques underwent five four‐week treatments of dextran sodium sulfate (DSS)‐distilled water (DW), which induced mild–moderate colitis with remission during each treatment cycle. Balloon rectal distention (RD) was performed under anesthesia 14 weeks after the final DSS‐DW treatment. Colonoscopy confirmed the absence of colitis prior to the start of RD. In naïve, untreated macaques, 10, 20 and 30 ml RD did not evoke brain activation. However, insular cortex/somatosensory II cortex and cerebellum were significantly activated in DSS‐treated macaques at 20 and 30 ml rectal distention. Intra‐rectal pressure after DSS treatment was not significantly different from that of naïve, untreated macaques, indicating lack of alteration of rectal functioning following DSS‐treatment. Treatment with 5‐HT3 receptor antagonist alosetron (p.o.) reduced distension‐evoked brain activation and decreased intra‐rectal pressure. The current findings demonstrated activation of brain regions to RD following DSS treatments which was not present in naïve macaques, suggesting visceral hypersensitivity. Brain activation in turn was reduced by alosetron, which could underlie the analgesic effect alosetron in IBS patients.
“…35 Under propofol anesthesia, contralateral Ins/SII activation was observed with fMRI. 35 Thus, the von Frey filaments used in the current study, even though they evoked responses in awake uninjured macaques, can be considered non-noxious. Extracellular recordings of dorsal horn spinothalamic tract (STT) neurons have shown responding to a similar range of von Frey filaments when applied to the macaque foot, but these were not as robust to in response to either pressure or pinch.…”
In vivo neuroimaging could be utilized as a noninvasive tool for elaborating the CNS mechanism of chronic pain and for elaborating mechanisms of potential analgesic therapeutics. A model of unilateral peripheral neuropathy was developed in the cynomolgus macaque, a species that is phylogenetically close to humans. Nerve entrapment was induced by placing a 4 mm length of polyvinyl cuff around the left common sciatic nerve. Prior to nerve injury, stimulation of the foot with a range of non-noxious von Frey filaments (1, 4, 8, 15, and 26 g) did not evoke brain activation as observed with functional magnetic resonance imaging (fMRI). Two weeks after injury, stimulation of the ipsilateral foot with non-noxious filaments activated the contralateral insula/secondary somatosensory cortex (Ins/SII) and anterior cingulate cortex (ACC). By contrast, no activation was observed with stimulation of the contralateral foot. Robust bilateral activation of thalamus was observed three to five weeks after nerve injury. Treatment with the clinical analgesic pregabalin reduced evoked activation of Ins/SII, thalamus and ACC whereas treatment with the NK1 receptor antagonist aprepitant reduced activation of the ipsilateral (left) thalamus. Twelve to 13 weeks after nerve injury, treatment with pregabalin reduced evoked activation of all regions of interest (ROI). By contrast, brain activation persisted in most ROI, except the ACC, following aprepitant treatment. Activation of the contralateral Ins/SII and bilateral thalamus was observed six months after nerve injury and pregabalin treatment suppressed activation of these nuclei. The current findings demonstrated persistent changes in CNS neurons following nerve injury as suggested by activation with non-painful mechanical stimulation. Furthermore, it was possible to functionally distinguish between a clinically efficacious analgesic drug, pregabalin, from a drug that has not demonstrated significant clinical analgesic efficacy, aprepitant. In vivo neuroimaging in the current nonhuman model could enhance translatability.
“…With respect to pain perception, a preclinical fMRI study in macaques found that noxious stimuli resulted in activation of the secondary somatosensory cortex and insula under propofol or pentobarbital anesthesia, whereas no activation was observed with isoflurane anesthesia. 40 In humans, ongoing nociceptive processing has been shown to occur in adolescent patients under balanced general anesthesia. 41 …”
Section: State Ii: Perioperative Approachesmentioning
confidence: 99%
“… 68 , 69 The two regions respond in an inverse manner to pain/nociception (mPFC deactivates and SI activates), thereby providing a suitable anticorrelative marker. The premise of our approach to the use of fNIRS during surgery is based on a number of themes: (1) animal, 70 including nonhuman primate 40 and human data 58 indicate that the pain pathways may be activated in the SI even under inhalational 71 and propofol 72 anesthesia; (2) surgical intervention, a controlled timed event, results in the potential initiation of chronic pain in a significant number of patients; (3) evaluation and response to pain during surgery are somewhat subjective and not based on specific/objective measures; and (4) an objective marker that allows for ongoing analgesia or immediate response to pain during the intra- and postoperative periods may provide an opportunity for diminished postoperative pain levels and risk of chronification (acute and chronic). Figure 2.…”
Section: State Ii: Perioperative Approachesmentioning
Chronic postsurgical pain (CPSP) results from a cascade of events in the peripheral and central nervous systems following surgery. Several clinical predictors, including the prior pain state, premorbid psychological state (e.g., anxiety, catastrophizing), intraoperative surgical load (establishment of peripheral and central sensitization), and acute postoperative pain management, may contribute to the patient’s risk of developing CPSP. However, research on the neurobiological and biobehavioral mechanisms contributing to pediatric CPSP and effective preemptive/treatment strategies are still lacking. Here we evaluate the perisurgical process by identifying key problems and propose potential solutions for the pre-, intra-, and postoperative pain states to both prevent and manage the transition of acute to chronic pain. We propose an eight-step process involving preemptive and preventative analgesia, behavioral interventions, and the use of biomarkers (brain-based, inflammatory, or genetic) to facilitate timely evaluation and treatment of premorbid psychological factors, ongoing surgical pain, and postoperative pain to provide an overall improved outcome. By achieving this, we can begin to establish personalized precision medicine for children and adolescents presenting to surgery and subsequent treatment selection.
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