Role of Nociceptor Toll-like Receptor 4 (TLR4) in Opioid-Induced Hyperalgesia and Hyperalgesic Priming

Abstract

In addition to analgesia, opioids produce opioid-induced hyperalgesia (OIH) and neuroplasticity characterized by prolongation of inflammatory-mediator-induced hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that hyperalgesia and priming induced by opioids are mediated by similar nociceptor mechanisms. In male rats, we first evaluated the role of nociceptor Toll-like receptor 4 (TLR4) in OIH and priming induced by systemic low-dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 mRNA (TLR4 AS-ODN) prevented OIH and prolongation of prostaglandin E 2 hyperalgesia (priming) induced by LDM. In contrast, high-dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which was attenuated by TLR4 AS-ODN. Protein kinase C (PKC) AS-ODN also prevented LDM-induced hyperalgesia and priming, whereas analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4 ϩ and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, whereas OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKC, HDM-induced analgesia, and priming are neither TLR4 nor PKC dependent. OIH produced by LDM is mediated by both IB4 ϩ and peptidergic nociceptors, whereas priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4 ϩ and peptidergic nociceptors. Implications for the use of low-dose opioids combined with nonopioid analgesics and in the treatment of opioid use disorder are discussed.

Involvement of TACAN, a Mechanotransducing Ion Channel, in Inflammatory But Not Neuropathic Hyperalgesia in the Rat

“…52,59,60 Rats were placed in cylindrical acrylic restrainers, with lateral ports that allowed access to the hind paw for nociceptive threshold testing. 9 They were acclimatized to the testing procedure prior to experimental manipulations. Mechanical nociceptive threshold is defined as the force in grams at which a rat withdrew its paw; and baseline threshold was defined as the mean of three readings taken before injection of test agents.…”

<p>Electroacupuncture Regulates Pain Transition by Inhibiting the mGluR5-PKCϵ Signaling Pathway in the Dorsal Root Ganglia</p>

“…11,12 Recent studies have found that PKCε is also involved in the process of pain transition. [13][14][15][16] PKCε inhibitors can effectively prevent the occurrence of pain transition and modulate the long-term and severe chronic pain caused by this process, which is clearly separate from tissue damage. 14,17,18 However, the upstream pathway that is involved in pain transition remains an open question.…”

In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia

“…We have recently shown that depending on the opioid used, and its dose and route of administration, opioids are capable of inducing acute hyperalgesia, even after a single administration (Araldi et al, 2015(Araldi et al, , 2018b(Araldi et al, ,c, 2019Ferrari et al, 2019). In particular, clinically used -opioid receptor (MOR) agonists, fentanyl (Araldi et al, 2018c) and morphine (Araldi et al, 2019;Ferrari et al, 2019), as well as the highly selective MOR agonist, DAMGO (Araldi et al, 2015(Araldi et al, , 2017(Araldi et al, , 2018a, produce OIH and hyperalgesic priming, a form of nociceptor neuroplasticity characterized by a persistent increase in responsivity of nociceptors to proalgesic mediators (Ferrari et al, 2010;Joseph and Levine, 2010b;Alvarez et al, 2014;Araldi et al, 2015;Khomula et al, 2017). Recent evidence has implicated a role of the action of MOR agonists on primary afferent nociceptors in OIH (Corder et al, 2017).…”