Neuronal pain pathway
The present invention relates to the discovery of a novel molecular pathway involved in long-term hyperexcitability of sensory neurons, which, in higher animals, is associated with persistent pain. It is based on the discovery that, following injury to an axon of a neuron, an increase in nitric oxide synthase activity results in increased nitric oxide production, which, in turn, activates guanylyl cyclase, thereby increasing levels of cGMP. Increased cGMP results in activation of protein kinase G (“PKG”), which then is retrogradely transported along the axon to the neuron cell body, where it phosphorylates MAPKerk.
1. A transdermal device comprising a protein kinase G (PKG) inhibitor according to Formula I, in an amount effective to inhibit long-term hyperexcitability in a damaged sensory neuron, or to treat chronic neuropathic pain, in a subject in need thereof:
wherein n is 1; Z is N;
wherein X represents
wherein Y represents
wherein A represents an un-substituted heteroaryl group;
wherein R, R1, R2, R4 and R5 are hydrogen;
wherein R3 is
wherein R6 and R9 are lower-alkoxy, R7 and R8 are hydrogen, and R10 is halogen.
2. The transdermal device of claim 1 , wherein the compound of formula I is linked to a transport peptide.
3. The transdermal device of claim 1 , wherein the transdermal device is a patch.