Macrophage Migration Inhibitory Factor (MIF) Makes Complex Contributions to Pain-Related Hyperactivity of Nociceptors after Spinal Cord Injury.

Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). While SCI pain mechanisms are often assumed to be in the central nervous system, rodent studies have revealed mechanistic contributions from primary nociceptors. These neurons become chronically hyperexcitable after SCI, generating ongoing electrical activity (OA) that promotes ongoing pain. A major question is whether extrinsic chemical signals help to drive OA after SCI. People living with SCI exhibit acute and chronic elevation of circulating levels of macrophage migration inhibitory factor (MIF), a cytokine implicated in preclinical pain models. Probable nociceptors isolated from male rats and exposed to a MIF concentration reported in human plasma (1 ng/ml) showed hyperactivity similar to that induced by SCI, although, surprisingly, a ten-fold higher concentration failed to increase excitability. Conditioned behavioral aversion to a chamber associated with peripheral MIF injection suggested that MIF stimulates affective pain. A MIF inhibitor, Iso-1, reversed SCI-induced hyperexcitability. Unlike after SCI, acute MIF-induced hyperexcitability was only partially abrogated by inhibiting ERK signaling. Unexpectedly, MIF concentrations that induced hyperactivity in nociceptors from Naïve animals, after SCI induced a long-lasting conversion from a highly excitable nonaccommodating type to a rapidly accommodating, hypoexcitable type, possibly as a homeostatic response to prolonged depolarization. Treatment with conditioned medium from cultures of dorsal root ganglion (DRG) cells obtained after SCI was sufficient to induce MIF-dependent hyperactivity in neurons from Naïve rats. Thus, changes in systemic and DRG levels of MIF may help to maintain SCI-induced nociceptor hyperactivity that persistently promotes pain.Significance Statement:Chronic neuropathic pain is a major challenge for people with spinal cord injury (SCI). Pain can drastically impair quality of life, and produces substantial economic and social burdens. Available treatments, including opioids, remain inadequate. This study shows that the cytokine macrophage migration inhibitory factor (MIF) can induce pain-like behavior and plays an important role in driving persistent ongoing electrical activity in injury-detecting sensory neurons (nociceptors) in a rat SCI model. The results indicate that SCI produces an increase in MIF release within sensory ganglia. Low MIF levels potently excite nociceptors, but higher levels trigger a long-lasting hypoexcitable state. These findings suggest that therapeutic targeting of MIF in neuropathic pain states may reduce pain and sensory dysfunction by curbing nociceptor hyperactivity.

The Effectiveness of High-Flow Nasal Oxygen During the Intraoperative Period: A Systematic Review and Meta-analysis.

BACKGROUND: High-flow nasal oxygen (HFNO) is increasingly being used in intensive care units for management of hypoxemia and respiratory failure. However, the effectiveness of HFNO for preventing hypoxemia in the intraoperative period is unclear. The purpose of this systematic review was to compare patient oxygenation and end-tidal CO2 (EtCO2), between HFNO and conventional oxygenation, during the intraoperative period in surgical patients. METHODS: Standard databases were searched from inception to February 2020. Studies involving intraoperative use of HFNO with 1 of the 4 outcomes: (1) oxygen (O2) desaturation, (2) minimum O2 saturation, (3) safe apnea time, or (4) EtCO2 were included. Intraoperative period was divided into 2 phases: at induction with general anesthesia and during surgical procedure under sedation without tracheal intubation. RESULTS: Eight randomized controlled trials (RCTs; 4 induction, 4 procedure, 2314 patients) were included for systematic review and meta-analyses. We found the risk of intraoperative O2 desaturation was lower in HFNO versus conventional oxygenation control group; at induction with an odds ratio (OR; 95% confidence interval [CI]) of 0.06 (0.01-0.59, P = .02), and during procedure, OR (95% CI) of 0.09 (0.05-0.18; P < .001). The minimum O2 saturation was higher in HFNO versus conventional oxygenation; at induction by a mean difference (MD) (95% CI) of 5.1% (3.3-6.9; P < .001), and during procedure, by a MD (95% CI) of 4.0% (1.8-6.2; P < .001). Safe apnea time at induction was longer in HFNO versus conventional oxygenation by a MD (95% CI) of 33.4 seconds (16.8-50.1; P < .001). EtCO2 at induction was not significantly different between HFNO and conventional oxygenation groups. CONCLUSIONS: This systematic review and meta-analysis show that, in the intraoperative setting, HFNO compared to conventional oxygenation reduces the risk of O2 desaturation, increases minimum O2 saturation, and safe apnea time. HFNO should be considered for anesthesia induction and during surgical procedures under sedation without tracheal intubation in patients at higher risk of hypoxemia.

Sham surgeries for central and peripheral neural injuries persistently enhance pain-avoidance behavior as revealed by an operant conflict test.

Studies using rodent models of neuropathic pain use sham surgery control procedures that cause deep tissue damage. Sham surgeries would thus be expected to induce potentially long-lasting postsurgical pain, but little evidence for such pain has been reported. Operant tests of voluntary behavior can reveal negative motivational and cognitive aspects of pain that may provide sensitive tools for detecting pain-related alterations. In a previously described operant mechanical conflict test involving lengthy familiarization and training, rodents freely choose to either escape from a brightly lit chamber by crossing sharp probes or refuse to cross. Here, we describe a brief (2-day) mechanical conflict protocol that exploits rats' innate exploratory response to a novel environment to detect persistently enhanced pain-avoidance behavior after sham surgeries for 2 neural injury models: thoracic spinal cord injury and chronic constriction injury of the sciatic nerve. Pitting the combined motivations to avoid the bright light and to explore the novel device against pain from crossing noxious probes disclosed a conflicting, hyperalgesia-related reluctance to repeatedly cross the probes after injury. Rats receiving standard sham surgeries demonstrated enhanced pain-like avoidance behavior compared with naive controls, and this behavior was similar to that of corresponding chronic constriction injury or spinal cord injury rats weeks or months after injury. In the case of sham surgery for spinal cord injury, video analysis of voluntary exploratory behavior directed at the probes revealed enhanced forepaw withdrawal responses. These findings have important implications for preclinical investigations into behavioral alterations and physiological mechanisms associated with postsurgical and neuropathic pain.