Toll-like receptor 4 signaling pathway in sensory neurons mediates remifentanil-induced postoperative hyperalgesia via transient receptor potential ankyrin 1

Abstract

Background: Remifentanil-induced postoperative hyperalgesia (RIH) refers to a state of hyperalgesia or aggravated pre-existing pain after remifentanil exposure. There has been considerable interest in understanding and preventing RIH. However, the mechanisms responsible for RIH are still not completely understood. Toll-like receptor 4 (TLR4), a classic innate immune receptor, has been detected in sensory neurons and participates in various nociceptive conditions, whereas its role in RIH remains unclear. Transient receptor potential ankyrin 1 (TRPA1) always serves as a nociceptive channel, whereas its role in RIH has not yet been investigated. This study aimed to determine whether the TLR4 signaling pathway in sensory neurons engaged in the development of RIH and the possible involvement of TRPA1 during this process. 
 Methods: A rat model of remifentanil-induced postoperative hyperalgesia (RIH) was established, which presented decreased paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). The mRNA and protein expression levels of TLR4, phosphorylated NF-κB, and TRPA1 in the dorsal root ganglion (DRG) from RIH model were analyzed by real-time PCR, western blot, and immunofluorescence. The TLR4 antagonist TAK-242 and the TRPA1 antagonist HC-030031 were applied to determine the role of sensory neuron TLR4 signaling and TRPA1 in RIH.
 Results: Compared with control, PWMT and PWTL were significantly decreased in RIH model. Moreover, the mRNA and protein expression of TLR4 and TRPA1 in DRG were upregulated after remifentanil exposure together with increased NF-κB phosphorylation. TLR4 antagonist TAK-242 mitigated mechanical pain in RIH together with downregulated expression of TLR4, phosphorylated NF-κB, and TRPA1 in DRG neurons. In addition, TRPA1 antagonist HC-030031 also alleviated mechanical pain and decreased TRPA1 expression in RIH without affecting TLR4 signaling in DRG. 
 Conclusions: Our results suggested that activation of TLR4 signaling pathway engaged in the development of RIH by regulating TRPA1 in DRG neurons. Blocking TLR4 and TRPA1 might serve as a promising therapeutic strategy for RIH.

Sensitization of human and rat nociceptors by low dose morphine is toll-like receptor 4-dependent

“… 13 Moreover, it has recently been reported that the mu-opioid analgesic, remifentanil, upregulates TLR4 expression in DRGs in the rat and decreases mechanical nociceptive threshold, an effect that is reversed by TAK-242, a TLR4 antagonist. 12 In fact, activation of TLR4 produces robust mechanical and thermal hyperalgesia, 44 – 47 and many opioids at ultra-low doses are TLR4 agonists. 13 , 48 Since sub-analgesic doses of opioids produce TLR4-dependent hyperalgesia, 13 , 48 , 49 the hyperalgesia induced by the repeated administration of opioids (OIH) could be due to desensitization of MOR (i.e., opioid tolerance), uncovering TLR4-dependent hyperalgesia.…”

“… 3 – 5 And, the systemic administration of sub-analgesic doses of opioid analgesics can, paradoxically, produce hyperalgesia (OIH), 6 an effect that is mediated either directly, by activation of TLR4, which is present on nociceptors, 7 , 8 or indirectly by the action of opioids at TLR4 on non-neuronal cells, including the immune system that, in turn, release pronociceptive mediators. 9 , 10 The primary afferent nociceptor has been suggested to play a key role in OIH, 11 which is attenuated by TLR4 antagonists, 12 as well as by intrathecal administration of an oligodeoxynucleotide (ODN) antisense for TLR4 mRNA. 13 Therefore, while opioids act as MOR agonists, to produce analgesia that is, in part, dependent on nociceptor MORs, 13 , 14 tolerance to MOR-dependent analgesia could unmask a hyperalgesic action of opioids, mediated by TLR4.…”

TRPA1 up‐regulation mediates oxidative stress in a pulpitis model in vitro

“…NF-κB activation by various signals resulted in up-regulation of TRPA1 channels in lung cancer cells (Sakamoto et al, 2023), HaCaT keratinocytes (Luostarinen et al, 2021), allergic contact dermatitis (Kang et al, 2017), and sensory neurons (X. Liu et al, 2023). In fibroblast-like synoviocytes, signalling by inflammatory cytokines, via NF-κB, resulted in a downstream activation of hypoxiainducible factor-1α (HIF1α) transcription factor which up-regulated TRPA1 expression (Hatano et al, 2012).…”

Sensitization of Human and Rat Nociceptors by Low Dose Morphine is TLR4-dependent

“…In behavioral studies we have previously shown that hyperalgesia induced by a systemic low, sub-analgesic dose of morphine, in rats, is nociceptor TLR4-dependent 2 . Moreover, it has recently been reported that the mu-opioid analgesic, remifentanil, upregulates TLR4 expression in DRGs in the rat and decreases mechanical nociceptive threshold, an effect that is reversed by TAK-242, a TLR4 antagonist 38 . In fact, activation of TLR4 produces robust mechanical and thermal hyperalgesia 4, 14, 48, 55 , and many opioids at ultra-low doses are TLR4 agonists 2, 23 .…”

“…And, the systemic administration of sub-analgesic doses of opioid analgesics can, paradoxically, produce hyperalgesia (OIH) 22 , an effect that is mediated either directly, by activation of TLR4, which is present on nociceptors 40, 53 , or indirectly by the action of opioids at TLR4 on non-neuronal cells, including cells of the immune system that, in turn, release pronociceptive mediators 37, 47 . The primary afferent nociceptor has been suggested to play a key role in OIH 9 , which is attenuated by TLR4 antagonists 38 , as well as by intrathecal administration of an oligodeoxynucleotide (ODN) antisense for TLR4 mRNA 2 . Therefore, while opioids act as MOR agonists, to produce analgesia that is, in part, dependent on nociceptor MORs 2, 16 , tolerance to MOR-dependent analgesia could unmask a hyperalgesic action of opioids, mediated by TLR4.…”