Methods, compositions, and kits for treating pain and pruritis

Abstract

The invention features a method for inhibiting one or more voltage-gated ion channels in a cell by contacting the cell with (i) a first compound that activates a channel-forming receptor that is present on nociceptors and/or pruriceptors; and (ii) a second compound that inhibits one or more voltage-gated ion channels when applied to the internal face of the channels but does not substantially inhibit said channels when applied to the external face of the channels, wherein the second compound is capable of entering nociceptors or pruriceptors through the channel-forming receptor when the receptor is activated. The invention also features a quarternary amine derivative or other permanently or transiently charged derivative of a compound that inhibits one or more voltage-gated ion channels when applied to the internal face of the channels but does not substantially inhibit said channels when applied to the external face of the channels.

1 . A method for treating pain or itch in a patient, said method comprising administering to said patient:
 (i) a first compound that activates a channel-forming receptor that is present on nociceptors and/or pruriceptors; and   (ii) a second compound that inhibits one or more voltage-gated ion channels when applied to the internal face of said channels but does not substantially inhibit said channels when applied to the external face of said channels, wherein said second compound is capable of entering nociceptors or pruriceptors through said channel-forming receptor when said receptor is activated.   
     
     
         2 . The method of  claim 1 , wherein said first compound activates a channel-forming receptor selected from TRPV1, P2X(2/3), TRPA1, and TRPM8. 
     
     
         3 . The method of  claim 2 , wherein said first compound is an activator of TRPV1 receptors, said activator selected from capsaicin, eugenol, arvanil (N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), Cl 8 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide), JYL79 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol, oleylgingerol, oleylshogaol, and SU200 (N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3 methoxybenzyl)thiourea). 
     
     
         4 . The method of  claim 2 , wherein said first compound is an activator of TRPA1 receptors, said activator selected from cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, mustard oil, and 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB 597). 
     
     
         5 . The method of  claim 2 , wherein said first compound is an activator of P2X receptors, said activator selected from ATP, 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, and ATPS′-O-(3-thiotriphosphate). 
     
     
         6 . The method of  claim 2 , wherein said first compound is an activator of TRPM8 receptors, said activator selected from menthol, iciclin, eucalyptol, linalool, geraniol, and hydroxycitronellal. 
     
     
         7 . The method of  claim 1 , wherein said second compound inhibits voltage-gated sodium channels. 
     
     
         8 . The method of  claim 7 , wherein said second compound is QX-314, N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine, pancuronium, or another low molecular weight, charged molecule that inhibits voltage-gated sodium channels when present inside of the cell. 
     
     
         9 . The method of claim 1 , wherein said second compound inhibits voltage-gated calcium, channels. 
     
     
         10 . The method of  claim 9 , wherein said compound is D-890 (quaternary methoxyverapamil), CERM 11888 (quaternary bepridil), or another low molecular weight, charged molecule that inhibits voltage-gated calcium channels when present inside of the cell. 
     
     
         11 . The method of claim 1 , wherein said second compound is a quaternary quartcrnary amine derivative or other charged derivative of a compound selected from riluzole, mexilitine, phenytoin, carbamazepine, procaine, tocainide, prilocaine, articaine, bupivicaine, mepivicine, diisopyramide, bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine, and fluspirilene. 
     
     
         12 . The method of claim 1 , wherein said pain is neuropathic pain, inflammatory pain, nociceptive pain, or procedural pain. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . A composition comprising:
 (i) a first compound that activates a channel-forming receptor that is present on nociceptors and/or pruriceptors; and   (ii) a second compound that inhibits one or more voltage-gated ion channels when applied to the internal face of said channels but does not substantially inhibit said channels when applied to the external face of said channels, wherein said second compound is capable of entering nociceptors or pruriceptors through said channel-forming receptor when said receptor is activated.   
     
     
         17 . The composition of  claim 16 , wherein said first compound activates a receptor selected from TRPV1, P2X(2/3), TRPA1, and TRPM8. 
     
     
         18 . The composition of  claim 16 , said composition formulated for oral, parenteral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intrathecal, epidural, or ocular administration, or by injection, inhalation, or direct contact with the nasal or oral mucosa. 
     
     
         19 . A method for inhibiting one or more voltage-gated ion channels in a cell, said method comprising contacting said cell with:
 (i) a first compound that activates a channel-forming receptor that is present on nociceptors and/or pruriceptors; and   (ii) a second compound that inhibits one or more voltage-gated ion channels when applied to the internal face of said channels but does not substantially inhibit said channels when applied to the external face of said channels, wherein said second compound is capable of entering nociceptors or pruriceptors through said channel-forming receptor when said receptor is activated.   
     
     
         20 . The method of  claim 19 , wherein said first compound activates a receptor selected from TRPV1, P2X(2/3), TRPA1, and TRPM8. 
     
     
         21 . A method for identifying a compound as being useful for the treatment of pain or itch, said method comprising the steps of:
 (a) contacting the external face of TRPV1, TRPA1, TRPM8, or P2X(2/3)-expressing neurons with:
 (i) a first compound that activates TRPV1, TRPA1, TRPM8 or P2X(2/3) receptors; and 
 (ii) a second compound that inhibits one or more voltage-gated ion channels when applied to the internal face of said channels but does not substantially inhibit said channels when applied to the external face of said channels, and 
   (b) determining whether said second compound inhibits said voltage-gated ion channels in said neurons,   wherein inhibition of said voltage-gated ion channels by said second compound identifies said second compound as a compound that is useful for the treatment of pain or itch.   
     
     
         22 . A quaternary amine derivative or other permanently or transiently charged derivative of a compound selected from riluzole, mexilitine, phenytoin, carbamazepine, procaine, articaine, bupivicaine, mepivicaine, tocainide, prilocaine, diisopyramide, bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine, fluspirilene, and a compound of any one of formulas (I)-(X). 
     
     
         23 . (canceled) 
     
     
         24 . A pharmaceutical composition comprising (i) a quaternary amine derivative or other permanently or transiently charged derivative of a compound of  claim 22 , and (ii) a pharmaceutically acceptable excipient. 
     
     
         25 . (canceled)