Nociceptin system as a target in sepsis?

Thomas, Roisin; Stover, Cordula M.; Lambert, David G.; Thompson, Jonathan P.

doi:10.1007/s00540-014-1818-6

Cited by 12 publications

(9 citation statements)

References 60 publications

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“…However, early recognition is not always easy as typical signs and symptoms are not always obvious in all critically ill patients. There has been a concerted effort from both clinical and basic researchers to address this issue of recognition with several studies attempting to establish early diagnostic criteria [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

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Sepsis and the orexin system

Hirota

2016

J Anesth

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receptors [10], and are synthesized mainly by neurons located in the posterolateral hypothalamus. OX1 receptors are widely distributed in the central nervous system (CNS), mostly in the ventromedial hypothalamus, and in peripheral tissues such as brown adipose tissue. OX2 receptors are also widely distributed in the CNS, mainly in the paraventricular nucleus, and in peripheral tissues such as the adrenal medulla [11]. The OXergic system plays an important role in several physiological functions such as feeding, sleep-wake cycle, locomotion, thermoregulation, autonomic function including cardiovascular function, and analgesia. OXergic system is particularly known to be involved in the control of the sympathetic nervous system [12]. In addition, the OXergic system contributes to the cardiovascular defense system which is attenuated in OX knockout mice and OX neuron-ablated mice [13]. Pathophysiology of sepsis and the OXergic system Sleep disorderPatients with sepsis in the intensive care unit (ICU) often show complete absence of the normal circadian rhythm pattern. Although rapid eye movement (REM) sleep typically occupies 20-25 % of nocturnal sleep in healthy subjects, patients with sepsis often show an absence or a decrease in REM sleep. It has been suggested that some specific mediators such as endotoxin may disrupt REM sleep [14]. Baracchi et al. [15] reported that septic rats showed suppression of REM sleep and δ-power during non-REM sleep and fragmented sleep during dark periods. Lipopolysaccharide (LPS) infusion significantly decreases OXergic neurons [7][8][9]. LPS infusion at 0.22 μg/h significantly reduced not only OX by 29.7 % but also REM sleep [7]. The sleepwake cycle returns to normal after recovery from sepsis.

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Section: Introductionmentioning

confidence: 99%

“…Several reports suggest that neuronal bioactive substances such as nociceptin [4] and endocanabinoid [6] may contribute to the pathophysiology of sepsis. Several reports [7][8][9] suggest that orexin (OX) may also be involved.…”

Section: Introductionmentioning

confidence: 99%

Sepsis and the orexin system

Hirota

2016

J Anesth

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“…Our results uncovered a novel anti-nociceptive phenotype in septic mice. Altered pain perception has previously been reported in sepsis patients (Thomas, Stover, Lambert, & Thompson, 2014), and increased sensitivity to deep pain but not cutaneous pain has been reported in studies of human experimental endotoxemia (Karshikoff et al, 2015).…”

Section: Discussionmentioning

confidence: 82%

Loss of tissue non-specific alkaline phosphatase (TNAP) enzyme activity in cerebral microvessels is coupled to persistent neuroinflammation and behavioral deficits in late sepsis

Nwafor¹,

Chakraborty

Brichacek

et al. 2019

Preprint

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Word Count: 7312Conflicts of Interest: The authors declare no conflicts of interest with the content of this article. Highlights• Alkaline phosphatase activity in brain microvessels is diminished in sepsis.• Loss of alkaline phosphatase activity is coupled to the loss of barrier integrity.• Brain infiltration of myeloid and T-lymphoid cells persists in late sepsis.• Septic mice exhibit a novel anti-nociceptive phenotype.• Cortical astrogliosis and microgliosis persist in late sepsis. AbstractSepsis is characterized as a host response to systemic inflammation and infection that may lead to multi-organ dysfunction and eventual death. While acute brain dysfunction is common among all sepsis patients, chronic neurological impairment is prevalent among sepsis survivors. The brain microvasculature has recently emerged as a major determinant of sepsis-associated brain dysfunction, yet the mechanisms that underlie its associated neuroimmune perturbations and behavioral deficits are not well understood.A growing body of data suggests that the loss of tissue nonspecific alkaline phosphatase (TNAP) enzyme activity in cerebral microvessels may be associated with changes in endothelial cell barrier integrity. The objective of this study was to determine the important mechanisms linking alterations in cerebrovascular TNAP enzyme activity to underlying neurological impairment in late sepsis. We hypothesized that the disruption of TNAP enzymatic activity in cerebral microvessels would be coupled to the sustained loss of brain microvascular integrity, elevated neuroinflammatory responses, and behavioral deficits. Male mice were subjected to cecal ligation and puncture (CLP), a model of experimental sepsis, and assessed up to seven days post-sepsis. All mice were observed daily for sickness behavior and underwent behavioral testing. Our results showed a significant decrease in brain microvascular TNAP enzyme activity in the somatosensory cortex and spinal cord of septic mice but not in the CA1 and CA3 hippocampal regions.Analyses of whole brain myeloid and T-lymphoid cell populations also revealed a persistent elevation of infiltrating leukocytes, which included both neutrophil and monocyte myeloid derived suppressor cells (MDSCs). Regional analyses of the somatosensory cortex, hippocampus, and spinal cord revealed significant astrogliosis and microgliosis in the cortex and spinal cord of septic mice that was accompanied by significant microgliosis in the CA1 and CA3 hippocampal regions. Assessment of behavioral deficits revealed no changes in learning and memory or evoked locomotion.However, the hot plate test uncovered a novel anti-nociceptive phenotype in our septic mice, and we speculate that this phenotype may be a consequence of sustained GFAP astrogliosis and loss of TNAP activity in the somatosensory cortex of septic mice. Taken together, these results demonstrate that the loss of TNAP enzyme activity in cerebral microvessels during late sepsis is coupled to sustained neuroimmune dysfunction which may underlie, in part, th...

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“…Recent studies have reported that the nociceptin/orphanin FQ peptide (NOP) opioid receptor and its endogenous agonist, Noc, are involved in sepsis and the observed inflammatory responses [ 16 , 17 ]. Thus, we next examined the Noc concentration-response relationships for both groups of CSMG neurons.…”

Section: Resultsmentioning

confidence: 99%

Modulation of Voltage-Gated Ca2+ Channels by G Protein-Coupled Receptors in Celiac-Mesenteric Ganglion Neurons of Septic Rats

et al. 2015

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Septic shock, the most severe complication associated with sepsis, is manifested by tissue hypoperfusion due, in part, to cardiovascular and autonomic dysfunction. In many cases, the splanchnic circulation becomes vasoplegic. The celiac-superior mesenteric ganglion (CSMG) sympathetic neurons provide the main autonomic input to these vessels. We used the cecal ligation puncture (CLP) model, which closely mimics the hemodynamic and metabolic disturbances observed in septic patients, to examine the properties and modulation of Ca2+ channels by G protein-coupled receptors in acutely dissociated rat CSMG neurons. Voltage-clamp studies 48 hr post-sepsis revealed that the Ca2+ current density in CMSG neurons from septic rats was significantly lower than those isolated from sham control rats. This reduction coincided with a significant increase in membrane surface area and a negligible increase in Ca2+ current amplitude. Possible explanations for these findings include either cell swelling or neurite outgrowth enhancement of CSMG neurons from septic rats. Additionally, a significant rightward shift of the concentration-response relationship for the norepinephrine (NE)-mediated Ca2+ current inhibition was observed in CSMG neurons from septic rats. Testing for the presence of opioid receptor subtypes in CSMG neurons, showed that mu opioid receptors were present in ~70% of CSMG, while NOP opioid receptors were found in all CSMG neurons tested. The pharmacological profile for both opioid receptor subtypes was not significantly affected by sepsis. Further, the Ca2+ current modulation by propionate, an agonist for the free fatty acid receptors GPR41 and GPR43, was not altered by sepsis. Overall, our findings suggest that CSMG function is affected by sepsis via changes in cell size and α2-adrenergic receptor-mediated Ca2+ channel modulation.

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Nociceptin system as a target in sepsis?

Cited by 12 publications

References 60 publications

Sepsis and the orexin system

Sepsis and the orexin system

Loss of tissue non-specific alkaline phosphatase (TNAP) enzyme activity in cerebral microvessels is coupled to persistent neuroinflammation and behavioral deficits in late sepsis

Modulation of Voltage-Gated Ca2+ Channels by G Protein-Coupled Receptors in Celiac-Mesenteric Ganglion Neurons of Septic Rats

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