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.