Neuronal pain pathway
View Patent ↗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 method of treating chronic pain in a human subject suffering from peripheral nervous system hyperalgesia, comprising administering, to the subject, an effective amount of an RNAi that decreases the level of human protein kinase G-1 alpha (type-I alpha PKG) protein in the cell body of a sensory neuron in the peripheral nervous system of the subject, wherein the RNAi is administered to the location from which the pain arises, and wherein the human protein kinase G-1 alpha (type-I alpha PKG) amino acid sequence is as set forth in SEQ ID NO:54.
2. A method of treating chronic pain in a human subject suffering from peripheral nervous system hyperalgesia, comprising administering, to the subject, an effective amount of an agent that decreases the level of human protein kinase G protein in the cell body of a sensory neuron in the peripheral nervous system of the subject, wherein the agent is administered to the location from which the pain arises, wherein the agent is an antisense nucleic acid molecule or RNAi that inhibits expression of human protein kinase G, and wherein the human protein kinase G amino acid sequence is as set forth in SEQ ID NO:54.
3. A method of inhibiting long-term hyperexcitability in the cell body of a sensory neuron in the peripheral nervous system of a human subject, comprising administering, to the subject, an effective amount of an agent that decreases the level of human protein kinase G protein in the cell body of the sensory neuron in the peripheral nervous system of the subject, wherein the agent is an RNAi that inhibits expression of human protein kinase G, and wherein the human protein kinase G amino acid sequence is as set forth in SEQ ID NO:54.
4. A method of inhibiting long-term hyperexcitability in the cell body of a sensory neuron in the peripheral nervous system of a human subject, comprising administering, to the subject, an effective amount of an agent that decreases the level of human protein kinase G protein in the cell body of the sensory neuron in the peripheral nervous system of the subject, wherein the agent is an antisense nucleic acid molecule that inhibits expression of human protein kinase G, and wherein the human protein kinase G amino acid sequence is as set forth in SEQ ID NO:54.
5. The method of any one of claims 1 , 2 , 3 , or 4 , wherein the sensory neuron is a human sensory neuron.
6. The method of claim 1 , wherein the RNAi is administered topically.
7. The method of claim 1 , wherein the RNAi is administered by local injection.
8. The method of claim 2 , 3 , or 4 , wherein the agent is administered topically.
9. The method of claim 2 , 3 , or 4 , wherein the agent is administered by local injection.