Method of treatment or prophylaxis inftammatory pain

Abstract

A method of treatment, reversal and/or symptomatic relief of inflammatory pain, including hyperalgesia, thermal or mechanical allodynia, in vertebrate animals, particularly in human subjects, comprising administering angiotensin II receptor 2 (AT 2 receptor) antagonists is disclosed. The AT 2 receptor antagonist may be provided alone or in combination with other compounds such as those that are useful in the control of inflammatory pain.

What is claimed is: 
     
         1 . A method for the treatment or prophylaxis of an inflammatory pain in a subject, comprising administering to the subject in need thereof an effective amount of an AT 2  receptor antagonist. 
     
     
         2 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is selected from small molecules, nucleic acids, peptides, polypeptides and peptidomimetics. 
     
     
         3 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is selected from compounds represented by the formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are independently selected from H, benzyl, substituted benzyl, phenyl, substituted phenyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, and heteroaryl, providing that both R 1  and R 2  are not hydrogen, 
 R 4  is selected from a carboxylate, carboxylic acid, sulfate, phosphate, sulfonamide, phosphonamide or amide, 
 X is selected from CH, nitrogen, sulfur or oxygen with the proviso that when X is sulfur or oxygen one of R 1  or R 2  is absent, 
 Y is selected from sulfur, oxygen or N—R N , where R N  is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 , 
 G is a five or six membered, homoaromatic or unsaturated, substituted or unsubstituted, heterocyclic ring including but not limited to the following rings systems: 
 
       
       
         
           
           
               
               
           
         
         
           where the symbol ‘*’ indicates the bond shared between the fused rings ‘A’ and ‘G’, 
           R 5  is selected from H, C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, C 1-6 alkoxy, or substituted C 1-6 alkoxy, 
           R 6  and R 8  are independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, benzylamino, biphenyl, substituted biphenyl, biphenyloxy, substituted biphenyloxy, naphthyl, substituted naphthyl, provided that one of R 6  or R 8  is not hydrogen, and 
           R 7  is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, naphthylmethylene, and substituted naphthylmethylene, 
         
         or a pharmaceutically compatible salt thereof. 
       
     
     
         4 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is selected from compounds represented by the formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are independently selected from H, phenyl, substituted phenyl, benzyl, substituted benzyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cyloalkyl, substituted C 3-6 cycloalkyl, heteroaryl, and substituted heteroaryl, substituted biphenylmethylene and saturated and unsaturated substituted biphenylmethylene, provided that one of R 1  or R 2  is not hydrogen, 
 R 4  is selected from a carboxylate, carboxylic acid, sulfate, phosphate, sulfonamide, phosphonamide or amide, 
 X is selected from CH, nitrogen, sulfur or oxygen with the proviso that when X is sulfur or oxygen one of R 1  or R 2  is absent, and 
 Y is selected from sulfur, oxygen or N—R N , where R N  is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 , 
 
         or a pharmaceutically compatible salt thereof. 
       
     
     
         5 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is selected from compounds represented by the formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2  and R 3  are independently selected from H, phenyl, substituted phenyl, benzyl, substituted benzyl, C 1-6 alkyl, substituted C 1-6 alkyl, with the proviso that at least one of R 1  or R 2  are not hydrogen, 
 X is selected from CH, nitrogen, sulfur or oxygen with the proviso that when X is sulfur or oxygen, one of R 1  or R 2  is absent, or is aryl or heteroaryl with the proviso that both R 1  and R 2  are absent, 
 V is selected from CH or nitrogen atom, 
 Y is selected from sulfur, oxygen or N—R N , where R N  is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 , 
 R 4  is selected from a carboxylate, carboxylic acid, sulfate, phosphate, sulfonamide, phosphonamide, or amide, 
 G is a five or six membered, homoaromatic or unsaturated, substituted or unsubstituted, heterocyclic ring including but not limited to the following rings systems: 
 
       
       
         
           
           
               
               
           
         
         
           where the symbol ‘*’ indicates the bond shared between the fused rings ‘A’ and ‘G’, 
           R 5  is selected from H, C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, or C 1-6 alkoxy, 
           R 6  and R 8  are independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, benzylamino, biphenyl, substituted biphenyl, biphenyloxy, substituted biphenyloxy, naphthyl, substituted naphthyl, provided that one of R 6  or R 8  is not hydrogen, and 
           R 7  is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, naphthylmethylene, and substituted naphthylmethylene, 
         
         or a pharmaceutically compatible salt thereof. 
       
     
     
         6 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is selected from compounds represented by the formula (IV): 
       
         
           
           
               
               
           
         
         wherein:
 R 10  is selected from H, halogen, C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, or C 1-6 alkoxy, 
 R 9  is selected from —NR 13 R 14 , wherein R 13  and R 14  are independently selected from C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 ; a five or six membered, saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring including but not limited to: 
 
       
       
         
           
           
               
               
           
         
         
           V is selected from CH or a nitrogen atom, 
           Y is selected from sulfur, oxygen or N—R N , where R N  is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 , 
           G is a five or six membered homoaromatic or heterocyclic, unsaturated, substituted ring including but not limited to the following rings systems: 
         
       
       
         
           
           
               
               
           
         
         
           where the symbol ‘*’ indicates the bond shared between the fused rings ‘A’ and ‘G’, 
           R 5  is selected from C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, or C 1-6 alkoxy, 
           R 6  and R 8  are independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, benzylamino, biphenyl, substituted biphenyl, biphenyloxy, substituted biphenyloxy, naphthyl, substituted naphthyl, provided that one of R 6  or R 8  is not hydrogen, and 
           R 7  is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, naphthylmethylene, and substituted naphthylmethylene, 
         
         or a pharmaceutically compatible salt thereof. 
       
     
     
         7 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is selected from compounds represented by the formula (V): 
       
         
           
           
               
               
           
         
         wherein:
 M is H or a halogen (fluoro, bromo, iodo, chloro), 
 R 5  is selected from C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, or C 1-6 alkoxy, 
 R 16  is selected from C 1-6 alkylamino, C 1-6 dialkylamino, substituted C 1-6 alkylamino, substituted C 1-6 dialkylamino, arylamino, diarylamino, substituted arylamino, substituted diarylamino, alkylarylamino, dialkylarylamino, substituted alkylarylamino, substituted dialkylarylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, dicycloalkylamino, diheteroarylamino, alkylcarbonylamino, arylcarbonylamino, alkylarylcarbonylamino, cycloalkylcarbonylamino, and 
 R 17  is selected from C 1-6 alkyl, substituted C 1-6 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, heteroaryl, or substituted heteroaryl, 
 
         or a pharmaceutically compatible salt thereof. 
       
     
     
         8 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is selected from peptide compounds represented by the formula (VIII):
   R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -Pro-R 7   (VIII)
   wherein:
 R 1  is absent or is selected from hydrogen, succinyl, L-aspartyl, sarcosyl, L-seryl, succinamyl, L-propyl, glycyl, L-tyrosyl, N α -nicotinoyl-tyrosyl, or D- or L-asparagyl; 
 R 2  is selected from arginyl or N-benzoylcarbonyl arginyl; 
 R 3  is absent or valyl; 
 R 4  is absent or is selected from L-phenylalanyl or L-tyrosyl; 
 R 5  is selected from valyl, L-isoleucyl, L-alanyl or L-lysyl; 
 R 6  is selected from L-histidyl, L-isoleucyl, L-tyrosyl or p-aminophenylalanyl; and 
 R 7  is selected from L-alanine, L-tyrosine, L- or D-leucine, glycine, L-isoleucine or □-alanine residue; 
   or a pharmaceutically compatible salt thereof.   
     
     
         9 . A method according to  claim 3 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (IX): 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from CH or nitrogen, 
 R 1  and R 2  are independently selected from phenyl, substituted phenyl, benzyl, substituted benzyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl and heteroaryl, 
 R 5  is selected from hydrogen, C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, C 1-6 alkoxy, and substituted C 1-6 alkoxy, and 
 R 7  is selected from is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, naphthylmethylene, and substituted naphthylmethylene. 
 
       
     
     
         10 . A method according to  claim 3 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (X): 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from CH or nitrogen, 
 R 1  and R 2  are independently selected from phenyl, substituted phenyl, benzyl, substituted benzyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl and heteroaryl, and 
 R 6  and R 8  are independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, benzylamino, biphenyl, substituted biphenyl, biphenyloxy, substituted biphenyloxy, naphthyl, substituted naphthyl, provided that one of R 6  or R 8  is not hydrogen. 
 
       
     
     
         11 . A method according to  claim 4 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (II), wherein R 1  and R 2  are independently selected from phenyl or substituted phenyl, C 1-6 alkyl, substituted biphenylmethylene, X is selected from CH or nitrogen and R 4  is a carboxylic acid. 
     
     
         12 . A method according to  claim 6 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (XI): 
       
         
           
           
               
               
           
         
         wherein:
 V is selected from CH or a nitrogen atom, 
 Y and W are independently selected from sulfur, oxygen or N—R N , where R N  is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 , 
 R 5  is selected from C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, or C 1-6 alkoxy, 
 R 7  is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, naphthylmethylene, and substituted napthylmethylene naphthylmethylene, 
 R 9  is selected from —NR 13 R 14 , wherein R 13  and R 14  are independently selected from C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 ; a five or six membered, saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring including but not limited to: 
 
       
       
         
           
           
               
               
           
         
         
           and 
           R 10  is selected from H, halogen, C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, or C 1-6 alkoxy. 
         
       
     
     
         13 . A method according to  claim 9 , wherein the AT 2 receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (IX), wherein R 1  and R 2  are phenyl, X is CH, R 5  is hydrogen or C 1-4 alkyl, and R 7  is selected from substituted benzyl. 
     
     
         14 . A method according to  claim 39 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (IX), R 5  is hydrogen and R 7  is selected from 4-(N,N-dimethylamino)-3-methylbenzyl, 4-methoxy-3-methylbenzyl, 4-amino-3-methylbenzyl. 
     
     
         15 . A method according to  claim 10 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (X), wherein R 1  and R 2  are independently selected from phenyl or substituted phenyl, X is CH, R 4  is a carboxylic acid, R 6  is selected from C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, phenyl, phenyloxy, and R 8  is selected from H, phenyl, phenyloxy, benzyl, benzyloxy, benzylamino, biphenyl, substituted biphenyl, biphenyloxy, substituted biphenyloxy, naphthyl, and substituted naphthyl. 
     
     
         16 . A method according to  claim 12 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (XI) wherein V is CH, Y and W are oxygen, R 5  is selected from C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, or C 1-6 alkoxy, R 7  is selected from biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, naphthylmethylene, and substituted naphthylmethylene, R N  is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 , R 9  is selected from —NR 13 R 14 , wherein R 13  and R 14  are independently selected from C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, OH, or NH 2 ; a five or six membered, saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring including but not limited to: 
       
         
           
           
               
               
           
         
         and R 10  is selected from H, halogen, C 1-6 alkyl, phenyl, substituted phenyl, substituted C 1-6 alkyl, or C 1-6 alkoxy. 
       
     
     
         17 . A method according to  claim 12 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (XI) wherein V is CH, Y and W are oxygen, R 5  is selected from C 1-6 alkyl, substituted C 1-6 alkyl, or C 1-6 alkoxy, R 7  is selected from biphenylmethylene, substituted biphenylmethylene, naphthylmethylene, and substituted naphthylmethylene, R N  is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl, R 9  is selected from —NR 13 R 14 , wherein R 13  and R 14  are independently selected from C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C 1-4 alkylaryl, substituted C 1-4 alkylaryl; a five or six membered, saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring including but not limited to: 
       
         
           
           
               
               
           
         
         and R 19  is H. 
       
     
     
         18 . A method according to  claim 12 , wherein the AT 2  receptor antagonist is selected from compounds, or pharmaceutically compatible salts thereof, represented by the formula (XI) wherein R 7  is selected from a substituted biphenylmethylene group represented by formula (XII): 
       
         
           
           
               
               
           
         
         wherein:
 R H  is selected from hydrogen, —OH, —SH, —HN 2 , nitrile, CF 3 , halo (F, Cl, Br, I), —NO 2 , C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, and 
 R A  is selected from C 1 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, aryl, —(C 1 -C 4 alkyl)aryl, heterocyclyl, heteroaryl, C 3 -C 7 -cycloalkyl, C 1 -C 4 -perfluoroalkyl, —OH, —SH, —HN 2 , nitrile, C 1 -C 10 -alkoxy, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C 1 -C 10 -alkylthio, —CF 3 , halo (F, Cl, Br, I), —NO 2 , —CO 2 R 23 , —NH 2 , C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, arylamino, diarylamino, arylC 1-4 alkylamino, arylC 1-4 dialkylamino, aryloxy, arylC 1-4 alkyloxy, formyl, C 1-10 alkylcarbonyl and C 1-10 alkoxycarbonyl, —PO 3 H 2 , —CO 2 H, —CONHSO 2 R 21 , —CONHSO 2 NHR 20 , —NHCONHSO 2 R 21 , —NHSO 2 R 21 , —NHSO 2 NHCOR 21 , —SO 2 NHR 20 , —SO 2 NHCOR 21 , —SO 2 NHCONHR 20 , —SO 2 NHCO 2 R 21 , tetrazolyl, —CHO, —CONH 2 , —NHCHO, —CO—(C 1 -C 6 perfluoroalkyl), —S(O) r —(C 1 -C 6  perfluoroalkyl), wherein R 20  is H, C 1 -C 5 -alkyl, aryl, —(C 1 -C 4 -alkyl)-aryl, heteroaryl; R 21  is aryl, C 3 -C 7 -cycloalkyl, C 1 -C 4 -perfluoroalkyl, C 1 -C 4 alkyl, optionally substituted with a substituent selected from the group consisting of aryl, heteroaryl, —OH, —SH, C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, —CF 3 , halo, —NO 2 , —CO 2 R 23 , —NH 2 , C 1 -C 4 -alkylamino, C 1 -C 4 -dialkylamino, —PO 3 H 2 , or heteroaryl; and R 22  is selected from C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, aryl, —(C 1 -C 5 -alkyl)-aryl, or heteroaryl. 
 
       
     
     
         19 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is an antigen-binding molecule that is immuno-interactive with an AT 2  receptor polypeptide. 
     
     
         20 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is a nucleic acid molecules that inhibits or otherwise reduces the level or functional activity of an expression product of an AT 2  gene. 
     
     
         21 . A method according to  claim 20 , wherein the AT 2  receptor antagonist is an antisense molecule. 
     
     
         22 . A method according to  claim 20 , wherein the AT 2  receptor antagonist is a ribozyme. 
     
     
         23 . A method according to  claim 20 , wherein the AT 2  receptor antagonist is an RNAi molecule. 
     
     
         24 . A method according to  claim 1 , wherein the AT 2  receptor antagonist is administered in the form of a composition comprising a pharmaceutically acceptable carrier or diluent. 
     
     
         25 . A method according to  claim 24 , wherein the composition is administered by a route selected from injection, topical application or the oral route, over a period of time and in an amount, which is effective to treat or prevent the inflammatory pain. 
     
     
         26 . A method according to  claim 1 , wherein the inflammatory pain results from an infection. 
     
     
         27 . A method according to  claim 26 , wherein the infection is selected from a viral, bacterial or fungal infection. 
     
     
         28 . A method according to  claim 1 , wherein the inflammatory pain results from a tissue burn. 
     
     
         29 . A method according to  claim 28 , wherein the tissue burn is selected from a burn of the cutaneous tissue and a sunburn. 
     
     
         30 . A method according to  claim 1 , wherein the inflammatory pain results from an autoimmune disease. 
     
     
         31 . A method according to  claim 30 , wherein the autoimmune disease is selected from rheumatoid arthritis, inflammatory arthritis, psoriasis, ankylosing spondylitis, osteoarthritis, colitis and irritable bowel disease. 
     
     
         32 . A method according to  claim 1 , wherein the inflammatory pain results from an inflammatory condition of a tissue or organ selected from skin, muscle, and joints. 
     
     
         33 . A method according to  claim 1 , wherein the inflammatory pain results from a cancer. 
     
     
         34 . A method according to  claim 1 , wherein the inflammatory pain results from a traumatic injury or surgery. 
     
     
         35 . A method for preventing or attenuating inflammatory pain in a subject, comprising administering to the subject an effective amount of an AT 2  receptor antagonist, which is optionally in the form of a composition comprising a pharmaceutically acceptable carrier and/or diluent. 
     
     
         36 . A method for producing analgesia in a subject having, or at risk of developing, a inflammatory pain, comprising administering to the subject an effective amount of an AT 2  receptor antagonist, which is optionally in the form of a composition comprising a pharmaceutically acceptable carrier and/or diluent. 
     
     
         37 . A method for identifying agents that antagonize an AT 2  receptor for treatment of inflammatory pain, comprising contacting a preparation with a test agent, wherein the preparation comprises (i) a polypeptide comprising an amino acid sequence corresponding to at least a biologically active fragment of an AT 2  receptor polypeptide, or to a variant or derivative thereof; or (ii) a polynucleotide that comprises at least a portion of a genetic sequence that regulates the expression of a gene that encodes an AT 2  receptor polypeptide, wherein the polynucleotide is operably linked to a reporter gene and detecting a decrease in the level or functional activity of the AT 2  receptor polypeptide, or an expression product of the reporter gene, relative to a normal or reference level or functional activity in the absence of the test agent, which indicates that the agent is an AT 2  receptor antagonist and is useful for the treatment of inflammatory pain. 
     
     
         38 . A method according to  claim 38 , comprising contacting a first sample of cells expressing an AT 2  receptor with an AT 2  receptor ligand and measuring a marker; contacting a second sample of cells expressing the AT 2  receptor with an agent and the ligand, and measuring the marker; and comparing the marker of the first sample of cells with the marker of the second sample of cells. 
     
     
         39 . A method according to  claim 38 , comprising measuring the levels of one or more markers, or combinations of markers associated with the activation of the AT 2  receptor or with the proliferation or differentiation of the cells. 
     
     
         40 . A method according to  claim 36 , wherein the marker or markers is/are selected from Zfhep expression, nitric oxide levels or nitric oxide synthase levels. 
     
     
         41 . A method according to  claim 36 , wherein the marker or markers is/are selected from Zfhep expression, nitric oxide levels or nitric oxide synthase levels, and the agent tests positive if it inhibits or otherwise reduces any one or more of Zfhep expression or the level of nitric oxide or the level or functional activity of nitric oxide synthase or the differentiation of the cells. 
     
     
         42 . A method of producing an agent for producing analgesia in a subject having, or at risk of developing, inflammatory pain, comprising testing an agent suspected of antagonizing an AT 2  receptor according to  claim 38 ; and synthesizing the agent on the basis that it tests positive for the antagonism. 
     
     
         43 . A method according to  claim 43 , further comprising derivatising the agent, and optionally formulating the derivatized agent with a pharmaceutically acceptable carrier or diluent, to improve the efficacy of the agent for treating or preventing inflammatory pain. 
     
     
         44 . A method according to  claim 3  wherein the compound of formula (I) is selected from:
 2-(Diphenylacetyl)-5-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (PD-126055) or an enantiomer thereof; 
 S(+)-1-[[4-(Dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo-[4,5-c]pyridine-6-carboxylic acid (PD-123,319); and 
 S(+)-1-[[4-hydroxy-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo-[4,5-c]pyridine-6-carboxylic acid (PD-121,981). 
 
     
     
         45 . A method according to  claim 45  wherein the AT 2  receptor antagonist is 2-(Diphenylacetyl)-5-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (PD-126055) or an enantiomer thereof.