GDNF hyperalgesia is mediated by PLCγ, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4‐binding protein versican

Abstract

The function of the isolectin B4 (IB4+)-binding and GDNF-dependent Ret (Ret+)-expressing non-peptidergic subpopulation of nociceptors remain poorly understood. We demonstrate that acute administration of GDNF sensitizes nociceptors and produces mechanical hyperalgesia in the rat. Intrathecal IB4-saporin, a selective toxin for IB4+/Ret+-nociceptors, attenuates GDNF but not NGF hyperalgesia. Conversely, intrathecal antisense to Trk A attenuated NGF but not GDNF hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides targeting mRNA for versican, the molecule that renders the Ret-expressing nociceptors IB4-positive (+), also attenuated GDNF but not NGF hyperalgesia, as did ADAMTS-4, a matrix metalloprotease known to degrade versican. Finally, inhibitors for all five signaling pathways known to be activated by GDNF at GFRa1/Ret: PLCc, CDK5, PI3K,MAPK/ERK and Src family kinases, attenuated GDNF hyperalgesia. Our results demonstrate a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF and suggest that the IB4-binding protein versican functions in the expression of this phenotype.

IB4(+) nociceptors mediate persistent muscle pain induced by GDNF

“…Consistent with reports of GDNF-induced cutaneous hyperalgesia (Bogen et al 2009;Bogen et al 2008;Ferrari et al 2010;Joseph and Levine 2010), a single intramuscular injection of GDNF produced a robust mechanical hyperalgesia, which lasted for at least 21 days. This hyperalgesia is mediated, at least in part, by nociceptor sensitization, since intramuscular injection of GDNF into the mechanical receptive field of A B C…”

“…While cutaneous GDNF-induced hyperalgesia is a wellestablished phenomenon Bogen et al 2008Bogen et al , 2009Ferrari et al 2010;Joseph and Levine 2010) and high levels of GDNF have been reported in painful neuromuscular diseases, studies of the role of GDNF in skeletal muscle nociception are lacking. The results of the present study indicate that GDNF produces a long-lasting muscle hyperalgesia mediated by action at IB4(ϩ) nociceptors.…”

“…The destruction of the IB4(ϩ) population of dorsal root ganglion neurons by intrathecal injection of a cytotoxin, saporin, conjugated to IB4 (IB4-saporin) has been established previously by us (Bogen et al 2009;Bogen et al 2008;Joseph et al 2008;Joseph and Levine 2010) and others (Nishiguchi et al 2004;Vulchanova et al 2001). IB4-saporin (Advanced Targeting Systems, San Diego, CA) was diluted with saline and a dose of 3.2 g in 20 l administered intrathecally 10 days before experiments Joseph and Levine 2010).…”

Extracellular matrix proteoglycan plays a pivotal role in sensitization by low pH of mechanosensitive currents in nociceptive sensory neurones

“…It was also reported in an in vivo experiment that hyperalgesia by GDNF involved versican (Bogen et al 2008). The latter authors speculated that glycosaminoglycan side chains of versican might interact with GDNF or soluble GFRα1 secreted by surrounding tissue, causing intracellular signal transduction via PLCγ and kinases mentioned above.…”

“…neurones Bogen et al 2008). To clarify any involvement of these intracellular signalling mechanisms in the low pH-induced sensitization, we examined the effects of a strong and broad-spectrum kinase inhibitor, staurosporine, and a phospholipase C inhibitor, U73122.…”