Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals

Abstract

Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both nociceptor terminals, we studied, in male Sprague Dawley rats, the effect of local administration of agents that reverse type I (protein translation) or type II [combination of Src and mitogen-activated protein kinase (MAPK)] priming. At the central terminal, priming induced by systemic, intradermal, or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, but at the peripheral terminal, it was reversed by the protein translation inhibitor. Mu-opioid receptor (MOR) antisense prevented fentanyl hyperalgesia and priming. To determine whether type I and II priming occur in the same population of neurons, we used isolectin B4-saporin or [Sar, Met(O)]-substance P-saporin to deplete nonpeptidergic or peptidergic nociceptors, respectively. Following intrathecal fentanyl, central terminal priming was prevented by both saporins, whereas that in peripheral terminal was not attenuated even by their combination. However, after intradermal fentanyl, priming in the peripheral terminal requires both peptidergic and nonpeptidergic nociceptors, whereas that in the central terminal is dependent only on peptidergic nociceptors. Pretreatment with dantrolene at either terminal prevented fentanyl-induced priming in both terminals, suggesting communication between central and peripheral terminals mediated by intracellular Ca signaling. application of fentanyl increased cytoplasmic Ca concentration in dorsal root ganglion neurons, which was prevented by pretreatment with dantrolene and naloxone. Therefore, acting at MOR in the nociceptor, fentanyl induces hyperalgesia and priming rapidly at both the central (type II) and peripheral (type I) terminal and this is mediated by Ca signaling. Fentanyl, acting at the μ-opioid receptor (MOR), induces hyperalgesia and hyperalgesic priming at both the central and peripheral terminal of nociceptors and this is mediated by endoplasmic reticulum Ca signaling. Priming in the central terminal is type II, whereas that in the peripheral terminal is type I. Our findings may provide useful information for the design of drugs with improved therapeutic profiles, selectively disrupting individual MOR signaling pathways, to maintain an adequate long-lasting control of pain.

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

“…Intrathecal administration of cordycepin and the combination of SU6656 and U0126 were performed in rats briefly anesthetized with 2.5% isoflurane (Phoenix Pharmaceuticals) in 97.5% O 2 using a 29-gauge hypodermic needle (300 unit/l syringe) inserted into the subarachnoid space, between the L4 and L5 vertebrae. The maximum intrathecal volume administered was 20 l; cordycepin (4 g) was dissolved in saline and injected intrathecally in a volume of 20 l; and, the intrathecal injection of the combination of SU6656 (10 g) and U0126 (10 g) was performed in a volume of 10 l each (Araldi et al, 2018c). Ten minutes after intrathecal treatments, fentanyl (1 g/5 l) was injected intradermally, on the dorsum of the hindpaw.…”

“…Systemic (subcutaneous) administration of fentanyl was performed at the nape of the neck (Araldi et al, 2018c). Rats received an injection of fentanyl (30 g/kg, s.c.) diluted in saline and administered subcutaneously (100 l/100 g body weight).…”

“…Recent evidence has implicated a role of the action of MOR agonists on primary afferent nociceptors in OIH (Corder et al, 2017). We have suggested a role of nociceptor calcium signaling in OIH (Araldi et al, 2018c). A MORindependent modulation of voltage-gated calcium channels and acid-sensing ion channels (ASICs) has also been implicated (Iegorova et al, 2010;Chizhmakov et al, 2015;Zaremba and Ruiz-Velasco, 2019).…”

“…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).…”

Perioperative opioid analgesia—when is enough too much? A review of opioid-induced tolerance and hyperalgesia

“…While Src inhibitors are not anti-nociceptive in acute pain (30), they reduce hyperalgesia in rodent models of OIH, neuropathic, inflammatory and bone cancer pain (102)(103)(104). Hyperalgesia is associated with Src-mediated phosphorylation and up-regulation of NMDA receptors, which leads to enhanced excitatory transmission in spinal neurones (105).…”