Increased Hyperalgesia and Proinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion After Surgery and/or Fentanyl Administration in Rats

Abstract

BACKGROUND:Perioperative fentanyl has been reported to induce hyperalgesia and increase postoperative pain. In this study, we tried to investigate behavioral hyperalgesia, the expression of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and the activation of microglia in the spinal cord and dorsal root ganglion (DRG) in a rat model of surgical plantar incision with or without perioperative fentanyl.METHODS:Four groups of rats (n = 32 for each group) were subcutaneously injected with fentanyl at 60 μg/kg or normal saline for 4 times with 15-minute intervals. Plantar incisions were made to rats in 2 groups after the second drug injection. Mechanical and thermal nociceptive thresholds were assessed by the tail pressure test and paw withdrawal test on the day before, at 1, 2, 3, 4 hours, and on the days 1–7 after drug injection. The lumbar spinal cord, bilateral DRG, and cerebrospinal fluid of 4 rats in each group were collected to measure IL-1β, IL-6, and TNF-α on the day before, at the fourth hour, and on the days 1, 3, 5, and 7 after drug injection. The lumbar spinal cord and bilateral DRG were removed to detect the ionized calcium-binding adapter molecule 1 on the day before and on the days 1 and 7 after drug injection.RESULTS:Rats injected with normal saline only demonstrated no significant mechanical or thermal hyperalgesia or any increases of IL-1β, IL-6, and TNF-α in the spinal cord or DRG. However, injection of fentanyl induced analgesia within as early as 4 hours and a significant delayed tail mechanical and bilateral plantar thermal hyperalgesia after injections lasting for 2 days, while surgical plantar incision induced a significant mechanical and thermal hyperalgesia lasting for 1–4 days. The combination of fentanyl and incision further aggravated the hyperalgesia and prolonged the duration of hyperalgesia. The fentanyl or surgical incision upregulated the expression of IL-1β, IL-6, and TNF-α in the spinal cord and bilateral DRG for more than 7 days and increase of ionized calcium-binding adapter molecule 1 in the spinal cord. The combination of fentanyl and incision resulted in higher increase of IL-1β, IL-6, and TNF-α in the spinal cord and bilateral DRG.CONCLUSIONS:The surgical plantar incision with or without perioperative fentanyl induced significant mechanical and thermal hyperalgesia, an increased expression of IL-1β, IL-6, TNF-α in the spinal cord and DRG, and activation of microglia in the spinal cord.

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

“…These observations were based on the increased glia numbers or elevated expression of nuclear factors and protein kinases in these glial cells (95,(136)(137)(138). Similar indirect effects were reported for other opioids acting at MOP receptors, including remifentanil, fentanyl and buprenorphine (139)(140)(141). Agonists of DOP and KOP receptors have not been tested.…”

“…Nevertheless, it is unclear how opioids or N/OFQ would affect the glia, since the expression of opioid receptors in native glia is still debatable (see above), most of those studies did not directly examine the involvement of glial MOP or NOP receptors, OIH was observed in triple MOP, DOP, and KOP receptor knockout mice (143,144), and the effects of morphine on toll-like receptor 4 in glia remain controversial [reviewed by (133)]. Furthermore, except for Chang et al (141) who used postoperative pain model, all other studies exclusively tested naïve mice or rats. Additionally, opioids were used at unconventional ultra-low doses or high doses which exceeded the analgesic doses used in pathological pain models, they were sometimes injected repetitively every few minutes, and hyperalgesia was measured 12 h, 24 h or 4 days following the last dose, which indicates opioid withdrawal-induced hyperalgesia (95,105,(135)(136)(137)(138)(139)(140)(141)(142).…”

“…Furthermore, except for Chang et al (141) who used postoperative pain model, all other studies exclusively tested naïve mice or rats. Additionally, opioids were used at unconventional ultra-low doses or high doses which exceeded the analgesic doses used in pathological pain models, they were sometimes injected repetitively every few minutes, and hyperalgesia was measured 12 h, 24 h or 4 days following the last dose, which indicates opioid withdrawal-induced hyperalgesia (95,105,(135)(136)(137)(138)(139)(140)(141)(142). Therefore, these effects can be viewed in the context of dependence rather than pain management, which is in line with clinical findings [reviewed by (134,145)].…”

Intra-CA1 Administration of Minocycline Alters the Expression of Inflammation-Related Genes in Hippocampus of CCI Rats

“…Neuropathic pain is a chronic pain condition that is usually induced by peripheral nerve injury. Recent reports suggest that the inflammation-related cytokines accumulation in dorsal root ganglion, dorsal spinal cord, hippocampus, thalamus, and somatosensoric cortex are paralleled by pain responses in different animal models of neuropathic pain (Al-Amin et al, 2011; Sun et al, 2016; Chang et al, 2018; Liu et al, 2018). In the chronic constriction injury (CCI) and the spared nerve injury models of neuropathic pain in rats, an increase in interleukin 1 beta (IL-1β), interleukin 6 (IL-6), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF) was observed in most brain regions (Al-Amin et al, 2011).…”

NLRP3 inflammasome activation contributes to remifentanil-induced postoperative hyperalgesia via regulation of NMDA receptor NR1 subunit phosphorylation and GLT-1

“…IL-1β contributes to RIH via regulation of Phospho-NR1 and GLT-1 Recent studies suggest that neuroimmune signalling accompanies OIH. Chang reported that incisions and/or fentanyl administration increased the expression of IL-1β, IL-6 and TNF-α in the spinal cord [26].…”