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Role of GPCR (mu-opioid)–receptor tyrosine kinase (epidermal growth factor) crosstalk in opioid-induced hyperalgesic priming (type II)

Araldi, Dionéia; Ferrari, Luiz, F.; Levine, Jon, D.*

doi: 10.1097/j.pain.0000000000001155
Research Paper

Repeated stimulation of mu-opioid receptors (MORs), by an MOR-selective agonist DAMGO induces type II priming, a form of nociceptor neuroplasticity, which has 2 components: opioid-induced hyperalgesia (OIH) and prolongation of prostaglandin-E2 (PGE2)-induced hyperalgesia. We report that intrathecal antisense knockdown of the MOR in nociceptors, prevented the induction of both components of type II priming. Type II priming was also eliminated by SSP-saporin, which destroys the peptidergic class of nociceptors. Because the epidermal growth factor receptor (EGFR) participates in MOR signaling, we tested its role in type II priming. The EGFR inhibitor, tyrphostin AG 1478, prevented the induction of prolonged PGE2-induced hyperalgesia, but not OIH, when tested out to 30 days after DAMGO. However, even when repeatedly injected, an EGFR agonist did not induce hyperalgesia or priming. A phosphopeptide, which blocks the interaction of Src, focal adhesion kinase (FAK), and EGFR, also prevented DAMGO-induced prolongation of PGE2 hyperalgesia, but only partially attenuated the induction of OIH. Inhibitors of Src and mitogen-activated protein kinase (MAPK) also only attenuated OIH. Inhibitors of matrix metalloproteinase, which cleaves EGF from membrane protein, markedly attenuated the expression, but did not prevent the induction, of prolongation of PGE2 hyperalgesia. Thus, although the induction of prolongation of PGE2-induced hyperalgesia at the peripheral terminal of peptidergic nociceptor is dependent on Src, FAK, EGFR, and MAPK signaling, Src, FAK, and MAPK signaling is only partially involved in the induction of OIH.

We investigate the mechanisms for the induction of type II hyperalgesic priming (opioid-induced hyperalgesia and prolongation of PGE2 hyperalgesia), a form of nociceptor neuroplasticity.

Division of Neuroscience, Departments of Medicine and Oral Surgery, University of California, San Francisco, San Francisco, CA, USA

Corresponding author. Address: Division of Neuroscience, Departments of Medicine and Oral Surgery, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0440, USA. Tel.: 476-5108; fax: 476-6305. E-mail address: Jon.Levine@ucsf.edu (J. D. Levine).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received August 22, 2017

Received in revised form December 29, 2017

Accepted January 04, 2018

© 2018 International Association for the Study of Pain
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