Neuronal pain pathway
AssigneeThe Trustees of Columbia University in the City of New York
InventorsRichard Ambron, Ying-Ju Sung, Donald Landry, Shi-Xian Deng
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Abstract
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.
Claims90
A method of treating chronic pain in a subject suffering from peripheral nervous system hyperalgesia, comprising administering, to a sensory neuron in a dorsal root ganglion of the subject, an effective amount of an agent that decreases protein kinase G activity.
A method of treating chronic pain in a subject suffering from peripheral nervous system hyperalgesia, comprising administering, to a sensory neuron in a dorsal root ganglion of the subject, an effective amount of a peptide inhibitor of protein kinase G activity.
A method of treating chronic pain in a subject suffering from peripheral nervous system hyperalgesia, comprising administering, to a sensory neuron in a dorsal root ganglion of the subject, an effective amount of an agent having formula I:
- wherein n is 1, 2 or 3;
- Z is N or CH;
- wherein X represents one of the following functional groups:
- wherein Y represents one of the following functional groups:
- wherein A represents aryl or heteroaryl groups un-substituted or substituted by one or more lower-alkyl, lower-alkoxy, hydroxy, alkoxy, amimo, alkylamino or halogen groups such that, where A is an aryl or heteroaryl group,
- When Y is:
- A is:
- and
- When Y is:
- A is:
- wherein R is hydrogen, lower-alkyl, or amidino;
- wherein R1, R2, R4, R5 is independently hydrogen, hydroxyl, lower-alkoxy, amino, or halogen;
- and
- wherein R3 is alkyl, aryl, heteroaryl, alkoxy, aryloxy, or a group selected from the following:
- wherein R6-R10 are independently hydrogen, hydroxy, lower-alkyl, lower-alkoxy, halogen, trifluoromethyl, carboxy, alkoxycarbonyl, amino, alkylamino, alkylcarbonylamino, alkylsulfonylamino (e.g. CF3SO2NH—, CH3SO2NH—), and tetrazole.
A method of treating chronic pain in a subject suffering from peripheral nervous system hyperalgesia, comprising administering, to a sensory neuron in a dorsal root ganglion of the subject, an effective amount of an agent selected from the group consisting of:
- (i) an agent that inhibits neuronal nitric oxide synthase selected from the group consisting of NG-nitro-L-arginine methyl ester hydrochloride, L-thiocitrulline, and an antisense nucleic acid or RNAi that inhibits nNOS expression;
- (ii) an agent that decreases cellular nitric oxide;
- (iii) an agent that inhibits guanylyl cyclase selected from the group consisting of L-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and an antisense nucleic acid molecule or RNAi that inhibits expression of guanylyl cyclase;
- (iv) an agent that decreases cellular cyclic guanosine monophosphate;
- and
- (v) an agent that inhibits translocation of activated mitogen activated protein kinase-erk into the nucleus.
A method of inhibiting long-term hyperexcitability in a sensory neuron, comprising administering, to the sensory neuron, an effective amount of an agent that decreases protein kinase G activity.
A method of inhibiting long-term hyperexcitability in a sensory neuron, comprising administering, to the sensory neuron, an effective amount of a peptide inhibitor of protein kinase G activity.
A method of inhibiting long-term hyperexcitability in a sensory neuron, comprising administering, to the sensory neuron, an effective amount of an agent having formula I:
- wherein n is 1, 2 or 3;
- Z is N or CH;
- wherein X represents one of the following functional groups:
- wherein Y represents one of the following functional groups:
- wherein A represents aryl or heteroaryl groups un-substituted or substituted by one or more lower-alkyl, lower-alkoxy, hydroxy, alkoxy, amimo, alkylamino or halogen groups such that, where A is an aryl or heteroaryl group,
- When Y is:
- A is:
- and
- When Y is:
- A is:
- wherein R is hydrogen, lower-alkyl, or amidino;
- wherein R1, R2, R4, R5 is independently hydrogen, hydroxyl, lower-alkoxy, amino, or halogen;
- and
- wherein R3 is alkyl, aryl, heteroaryl, alkoxy, aryloxy, or a group selected from the following:
- wherein R6-R10 are independently hydrogen, hydroxy, lower-alkyl, lower-alkoxy, halogen, trifluoromethyl, carboxy, alkoxycarbonyl, amino, alkylamino, alkylcarbonylamino, alkylsulfonylamino (e.g. CF3SO2NH—, CH3SO2NH—), and tetrazole.
A method of inhibiting long-term hyperexcitability in a sensory neuron, comprising administering, to the sensory neuron, an effective amount of an agent selected from the group consisting of:
- (i) an agent that inhibits neuronal nitric oxide synthase selected from the group consisting of NG-nitro-L-arginine methyl ester hydrochloride, L-thiocitrulline, and an antisense nucleic acid or RNAi that inhibits nNOS expression;
- (ii) an agent that decreases cellular nitric oxide;
- (iii) an agent that inhibits guanylyl cyclase selected from the group consisting of L-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and an antisense nucleic acid molecule or RNAi that inhibits expression of guanylyl cyclase;
- (iv) an agent that decreases cellular cyclic guanosine monophosphate;
- and
- (v) an agent that inhibits translocation of activated mitogen activated protein kinase-erk into the nucleus.
A method of treating pain in a subject, where the pain is determined to be associated with a dorsal root ganglion at a particular spinal cord level, comprising topically applying a pain inhibitor comprising a transport peptide to skin lying within the dermatome corresponding to the spinal cord level associated with the pain.
A transdermal device containing an inhibitor of protein kinase G.
A transdermal device containing an effective amount of an agent having formula I:
- wherein n is 1, 2 or 3;
- Z is N or CH;
- wherein X represents one of the following functional groups:
- wherein Y represents one of the following functional groups:
- wherein A represents aryl or heteroaryl groups un-substituted or substituted by one or more lower-alkyl, lower-alkoxy, hydroxy, alkoxy, amimo, alkylamino or halogen groups such that, where A is an aryl or heteroaryl group,
- When Y is:
- A is:
- and
- When Y is:
- A is:
- wherein R is hydrogen, lower-alkyl, or amidino;
- wherein R1, R2, R4, R5 is independently hydrogen, hydroxyl, lower-alkoxy, amino, or halogen;
- and
- wherein R3 is alkyl, aryl, heteroaryl, alkoxy, aryloxy, or a group selected from the following:
- wherein R6-R10 are independently hydrogen, hydroxy, lower-alkyl, lower-alkoxy, halogen, trifluoromethyl, carboxy, alkoxycarbonyl, amino, alkylamino, alkylcarbonylamino, alkylsulfonylamino (e.g. CF3SO2NH—, CH3SO2NH—), and tetrazole.
A method of determining whether a test agent is an inhibitor of long-term hyperexcitability, comprising the following steps:
- (i) providing a test sensory neuron comprising an axonal segment;
- (ii) creating an injury in the axonal segment;
- (iii) administering the test agent to the test sensory neuron either prior to, concurrent with, or following the creation of the injury according to step (ii);
- and,
- (iv) determining whether the test agent inhibits an increase in the level of nitric oxide synthetase activity in the injured test sensory neuron,
- wherein an inhibition of an increase in the level of nitric oxide synthetase activity in the injured test sensory neuron indicates that the test agent is an inhibitor of long-term hyperexcitability.
A method of determining whether a test agent is an inhibitor of long-term hyperexcitability, comprising the following steps:
- (i) providing a test sensory neuron comprising an axonal segment;
- (ii) creating an injury in the axonal segment;
- (iii) administering the test agent to the test sensory neuron either prior to, concurrent with, or following the creation of the injury according to step (ii);
- and,
- (iv) determining whether the test agent inhibits an increase in the level of guanylyl cyclase activity in the injured test sensory neuron,
- wherein an inhibition of an increase in guanylyl cyclase activity in the injured test sensory neuron indicates that the test agent is an inhibitor of long-term hyperexcitability.
A method of determining whether a test agent is an inhibitor of long-term hyperexcitability, comprising the following steps:
- (i) providing a test sensory neuron comprising an axonal segment;
- (ii) creating an injury in the axonal segment;
- (iii) administering the test agent to the test sensory neuron either prior to, concurrent with, or following the creation of the injury according to step (ii);
- and,
- (iv) determining whether the test agent inhibits an increase in the level of protein kinase G activity in the injured test sensory neuron,
- wherein an inhibition of an increase in protein kinase G activity in the injured test sensory neuron indicates that the test agent is an inhibitor of long-term hyperexcitability.
A method of determining whether a test agent is an inhibitor of long-term hyperexcitability, comprising the following steps:
- (i) providing a test sensory neuron comprising an axonal segment;
- (ii) creating an injury in the axonal segment;
- (iii) administering the test agent to the test sensory neuron either prior to, concurrent with, or following the creation of the injury according to step (ii);
- and,
- (iv) determining whether the test agent inhibits transport of protein kinase G in the injured test sensory neuron,
- wherein inhibition of transport of protein kinase G in the injured sensory neuron indicates that the test agent is an inhibitor of long-term hyperexcitability.
A method of determining whether a test agent is an inhibitor of long-term hyperexcitability, comprising the following steps:
- (i) providing a test sensory neuron comprising an axonal segment;
- (ii) creating an injury in the axonal segment;
- (iii) administering the test agent to the test sensory neuron either prior to, concurrent with, or following the creation of the injury according to step (ii);
- and,
- (iv) determining whether the test agent inhibits an increase in phosphorylation of MAPKerk in the injured test sensory neuron,
- wherein inhibition of phosphorylation of MAPKerk in the injured sensory neuron indicates that the test agent is an inhibitor of long-term hyperexcitability.
A method of determining whether a test agent is an inhibitor of long-term hyperexcitability, comprising the following steps:
- (i) providing a test sensory neuron comprising an axonal segment;
- (ii) creating an injury in the axonal segment;
- (iii) administering the test agent to the test sensory neuron either prior to, concurrent with, or following the creation of the injury according to step (ii);
- and,
- (iv) determining whether the test agent inhibits translocation of MAPKerk into the nucleus of the injured sensory neuron,
- wherein inhibition of translocation of MAPKerk into the nucleus of the injured sensory neuron indicates that the test agent is an inhibitor of long-term hyperexcitability.
An isolated nucleic acid molecule comprising a nucleic acid molecule that is at least 90 percent homologous to a nucleic acid molecule having SEQ ID NO:9.
An isolated protein that is at least 90 percent homologous to a protein having amino acid sequence SEQ ID NO:10, and that has protein kinase activity.
A method of treating chronic pain in a subject, comprising administering, into the central nervous system of the subject, an effective amount of a peptide inhibitor of protein kinase G activity.
A method of treating chronic pain in a subject, comprising administering, into the central nervous system of the subject, an effective amount of an agent having formula I:
- wherein n is 1, 2 or 3;
- Z is N or CH;
- wherein X represents one of the following functional groups:
- wherein Y represents one of the following functional groups:
- wherein A represents aryl or heteroaryl groups un-substituted or substituted by one or more lower-alkyl, lower-alkoxy, hydroxy, alkoxy, amimo, alkylamino or halogen groups such that, where A is an aryl or heteroaryl group,
- When Y is:
- A is:
- and
- When Y is:
- A is:
- wherein R is hydrogen, lower-alkyl, or amidino;
- wherein R1, R2, R4, R5 is independently hydrogen, hydroxyl, lower-alkoxy, amino, or halogen;
- and
- wherein R3 is alkyl, aryl, heteroaryl, alkoxy, aryloxy, or a group selected from the following:
- wherein R6-R10 are independently hydrogen, hydroxy, lower-alkyl, lower-alkoxy, halogen, trifluoromethyl, carboxy, alkoxycarbonyl, amino, alkylamino, alkylcarbonylamino, alkylsulfonylamino (e.g. CF3SO2NH—, CH3SO2NH—), and tetrazole.
Dependencies are inferred from the claim text.