Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat

Abstract

Inflammatory processes occurring within the central nervous system (CNS) can produce 'illness induced behaviours' which include fever, sleep and the development of allodynia and hyperalgesia. Here we demonstrate the effects of the pro-inflammatory mediators, bacterial endotoxin, and rat recombinant interleukin 1 beta (rrIL-1 beta) or tumour necrosis factor-alpha (rrTNF alpha) on the integration of somatosensory information at the single neuronal level, via recordings from wide-dynamic range neurones in the dorsal horn of the spinal cord in anaesthetized rats. Intrathecal administration of E. coli lipopolysaccharide (LPS, 10 and 100 microg, i.t.) enhanced the activity of dorsal horn neurones, including facilitation of neuronal post-discharge. Intrathecal administration of IL-1 beta (5-5000 pg) or TNF-alpha (5-5000 pg) enhanced dorsal horn neuronal responses, including the acute responses to C-fibre stimulation, wind-up and post-discharge, however, the effects of IL-1 beta were more robust than those of TNF alpha. Intrathecal administration of IL-1 beta (1-1000 pg) also leads to the development of mechanical allodynia and hyperalgesia. On the other hand intrathecal application of TNF alpha did not produce changes in sensitivity to mechanical stimuli. Changes in the activity of spinal wide-dynamic range neurones induced by local inflammation may provide a pathomechanism for the clinical pathology of central pain syndrome, which can accompany CNS disease or acute CNS injury.

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

“…TNF␣ and IL-6 were significantly correlated with evoked pain measures in the PTSD group, whereas there was no correlation between proinflammatory cytokine concentrations and any pain measure in the CC group. CNS release of TNF␣ can lower pain thresholds by modulating the number of neuronal membrane ion channels and their functional activity (Choi et al, 2010), which can result in hyperexcitable pain circuits within dorsal horn (Reeve et al, 2000;Park et al, 2011;Kawasaki et al, 2008). TNF␣ binding to the microglial TNF␣ receptor (TNF␣-R) stimulates p38 mitogen-activated protein kinase (P38 MAPK) phosphorylation and activation.…”

“…Similar to TNF␣, both inflammatory and neuropathic pain models have shown that IL-1␤ is synthesized and secreted from astrocytes, neurons, and microglia. IL-1␤ enhances activity in the lamina II of the dorsal horn by multiple mechanisms (Reeve et al, 2000;Park et al, 2011;Kawasaki et al, 2008) and is known to amplify pain signaling. Increased IL-1␤ secretion in the PTSD-group may enhance pain nociception, which is a conclusion supported in our study by the following: 1) increases in spontaneously reported pain intensity and unpleasantness and 2) the increased evoked pain measure of temporal summation.…”

Microglia in the spinal cord and neuropathic pain

“…Inhibiting spinal p38 suppresses IL‐1β upregulation in the spinal cord of PNI animals93. C‐Fiber‐evoked responses, N‐methyl‐D‐aspartate receptor‐mediated responses, and wind‐up in wide‐dynamic‐range dorsal horn neurons are enhanced by IL‐1β94, 95. IL‐1β has also been reported to decrease γ‐aminobutyric acid  A receptor‐mediated currents96.…”

The roles of nerve growth factor and cholecystokinin in the enhancement of morphine analgesia in a rodent model of central nervous system inflammation

“…Previous work has shown that i.t. administration of LPS produces an enhanced production of cytokines such as tumour necrosis factor-α (TNF-α) in the cerebrospinal fluid (CSF) (Tanazawa et al, 1994), as well as significant thermal hyperalgesia and movement-evoked hyperalgesia (Meller et al, 1994;Kehl et al, 2004), and enhanced activity of dorsal horn neurons (Reeve et al, 2000). A two-injection LPS protocol consisting of a low dose "priming" i.t.…”