Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms

Abstract

We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced hyperalgesia and prolongation of prostaglandin-E2-induced hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming. Opioid receptor antagonist, naloxone, induced hyperalgesia in DAMGO-primed paws. When repeatedly injected, naloxone induced hyperalgesia, and hyperalgesic priming, supporting the suggestion that maintenance of priming involves changes in mu-opioid receptor (MOR) signaling. However, the knockdown of MOR with oligodeoxynucleotide antisense did not reverse priming. Mitogen-activated protein kinase (MAPK) and focal adhesion kinase, which are involved in the Src signaling pathway, previously implicated in type II priming, also inhibited the expression, but not maintenance of priming. However, when Src and MAPK inhibitors were co-administered, type II priming was reversed, in male rats. A second model of priming, latent sensitization, induced by complete Freund’s adjuvant (CFA) was also reversed, in males. In females, the inhibitor combination was only able to inhibit the expression and maintenance of DAMGO-induced priming when knockdown of G-protein-coupled estrogen receptor 30 (GPR30) in the nociceptor was performed. These findings demonstrate that the maintenance of DAMGO-induced type II priming and latent sensitization is mediated by an interaction between, Src and MAP kinases, which in females is GPR30 dependent.

A Src family kinase maintains latent sensitization in rats, a model of inflammatory and neuropathic pain

“…In contrast with our results, Araldi et al (2017; found that the SFK inhibitor SU-6656 did not inhibit CFA-induced latent sensitization at the relatively high dose of 27 nmol i.th.…”

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

“…Nociceptive threshold testing. Mechanical nociceptive threshold was measured using an Ugo Basile Analgesymeter (Randall-Selitto pawwithdrawal device, Stoelting), which applies a linearly increasing mechanical force to the dorsum of a rat's hindpaw, with a dome-shaped plinth, as described previously Araldi et al, 2015Araldi et al, , 2017Ferrari and Levine, 2015). Rats were placed in cylindrical acrylic restrainers that provide ventilation, and allow extension of the hind legs from lateral ports to assess nociceptive threshold, while minimizing restraint stress.…”

“…We have previously demonstrated that several inflammatory mediators, which act as agonists at cell surface receptors on nociceptor (Aley et al, 2000;Reichling and Levine, 2009;Bogen et al, 2012;Ferrari et al, 2013a,b) and MOR agonists (e.g., DAMGO, fentanyl, and morphine) (Araldi et al, 2015(Araldi et al, , 2017(Araldi et al, , 2018aFerrari et al, 2019), produce hyperalgesic priming, a form of nociceptor neuroplasticity thought to contribute to the transition from acute to chronic pain. A key feature of the primed nociceptor is that it responds to pronociceptive mediators, prototypically prostaglandin E 2 (PGE 2 ), with markedly enhanced and prolonged mechanical hyperalgesia (Aley et al, 2000;Parada et al, 2003bParada et al, , 2005Reichling and Levine, 2009;Ferrari et al, 2014Ferrari et al, , 2016Ferrari et al, , 2019Araldi et al, 2015Araldi et al, , 2017Araldi et al, , 2018aAraldi et al, ,c, 2019Khomula et al, 2017). Intradermal MOR agonists, in a dose that does not affect mechanical nociceptive threshold in opioid-naive rats, induces robust hyperalgesia in rats previously treated systemically with a MOR agonist (Araldi et al, 2018a).…”

“…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).…”

Subliminal (latent) processing of pain and its evolution to conscious awareness

“…This is defined as a prolonged latent hyper-responsiveness of nociceptors to inflammatory mediators subsequent to nerve damage (Aley et al, 2000; Kandasamy and Price, 2015; Reichling and Levine, 2009). The notion of hyperalgesic priming has also been applied as it relates to estrogen receptors (Ferrari et al, 2017b) and repeated opioid exposure (Araldi et al, 2017). We are unaware of evidence for similar processes in the CNS that may lead to covert processing of non-consciously perceived ‘stimuli’ that may lead to CNS hyperalgesic priming.…”