Isoform specific inhibition for treatment of pain and reduction of anesthetic threshold

• US 20030022866A1
• Filed: 06/28/2002
• Published: 01/30/2003
• Est. Priority Date: 12/08/1999
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Tao, Yuanxiang, Johns, Roger A.
• Granted Patent: US 7,030,100 B2
• Time in Patent Office: Days
• US Class Current: 514/81
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: C12Q 1/44 involving esterase
• CPC Class Codes: C12Q 1/485 involving kinase
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Abstract

Several lines of evidence have shown a role for the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway in the development of spinal hyperalgesia. However, the roles of effectors for cGMP are not fully understood in the processing of pain in the spinal cord. cGMP-dependent protein kinase (PKG) Iα but not PKGIβ was localized in the neuronal bodies and processes, and was distributed primarily in the superficial laminae of the spinal cord. Intrathecal administration of an inhibitor of PKGIα, Rp-8-[(4-Chlorophenyl)thio]-cGMPS triethylamine, produces significant antinociception. Moreover, PKGIα protein expression was dramatically increased in the lumbar spinal cord after noxious stimulation. This upregulation of PKGIα expression was completely blocked not only by a neuronal NO synthase inhibitor, and a soluble guanylate cyclase inhibitor, but also by an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Noxious stimulation not only initially activates but also later upregulates PKGIα expression in the superficial laminae via an NMDA-NO-cGMP signaling pathway, suggesting that PKGIα plays an important role in the central mechanism of inflammatory hyperalgesia in the spinal cord.

Claims

1. A method of affecting nociception, comprising:

administering to a patient in need thereof an analgesic amount of an inhibitor of cyclic guanosine monophosphate (cGMP)-dependent protein kinase Iα

(PKGIα

).

2. The method of claim 1 wherein said inhibitor preferentially inhibits isoenzyme I relative to isoenzyme II and inhibits isoform α

relative to isoform β

.

3. The method of claim 1 wherein the patient experiences chronic pain.

4. The method of claim 1 wherein the patient experiences acute pain.

5. The method of claim 1 wherein the patient experiences inflammatory hyperalgesia.

6. The method of claim 1 wherein the patient experiences spinal hyperalgesia.

7. The method of claim 1 wherein the patient is receiving anesthetic whereby upon administering said inhibitor the threshold for said anesthetic is reduced.

8. The method of claim 1 wherein the mode of administration is intrathecal.

9. The method of claim 1 wherein the inhibitor does not inhibit cAMP-dependent protein kinase or cGMP-dependent phosphodiesterases.

10. The method of claim 1 wherein the inhibitor is Rp-8-[(4-Chlorophenyl)thio]-cGMPS triethylamine (Rp-8-CPT-cGMPS).

37. The method of claim 1 further comprising administering an NMDA receptor inhibitor to the patient.

38. The method of claim 37 wherein the NMDA receptor inhibitor is ketamine.

39. The method of claim 37 wherein the NMDA receptor inhibitor is MK-801.

40. The method of claim 1 further comprising administering an inhibitor of neuronal nitric oxide synthase (nNOS) to the patient.

41. The method of claim 40 wherein the inhibitor of nNOS is N^G-nitro-L-arginine methyl ester (L-NAME).

42. The method of claim 40 wherein the inhibitor of nNOS is 7-nitroindazole.

43. The method of claim 40 wherein the inhibitor of nNOS is 3′

-bromo-7-nitro indazole.

44. The method of claim 1 further comprising administering an inhibitor of guanylyl cyclase.

45. The method of claim 44 wherein the inhibitor of guanylyl cyclase is ODQ.

46. The method of claim 44 wherein the inhibitior of guanylyl cyclase is methylene blue.

11. A method of affecting nociception, comprising:

administering intrathecally to a patient in need thereof an analgesic amount of Rp-8-[(4-Chlorophenyl)thio]-cGMPS triethylamine (Rp-8-CPT-cGMPS).

12. The method of claim 11 wherein the patient experiences acute pain.

13. The method of claim 11 wherein the patient experiences inflammatory hyperalgesia.

14. The method of claim 11 wherein the patient experiences spinal hyperalgesia.

15. The method of claim 11 wherein the patient is receiving anesthetic whereby upon administering said inhibitor the threshold for said anesthetic is reduced.

16. A catheter comprising an analgesic amount of an inhibitor of cyclic guanosine monophosphate (cGMP)-dependent protein kinase Iα

(PKGIα

).

17. The catheter of claim 16 wherein said inhibitor preferentially inhibits isoenzyme I relative to isoenzyme II and inhibits isoform a relative to isoform β

.

18. The catheter of claim 16 which is intrathecal.

19. The catheter of claim 16 wherein the inhibitor is Rp-8-CPT-cGMPS.

20. A pharmaceutical composition for treating pain comprising Rp-8-CPT-cGMPS in a sterile, pyrogen-free aqueous vehicle.

21. A pharmaceutical composition for treating pain comprising an inhibitor of cyclic guanosine monophosphate (cGMP)-dependent protein kinase Iα

(PKGIα

) in a sterile, pyrogen-free aqueous vehicle.

22. The pharmaceutical composition of claim 21 wherein said inhibitor preferentially inhibits isoenzyme I relative to isoenzyme II and inhibits isoform α

relative to isoform β

.

23. A method for screening for drugs useful in the treatment of pain, comprising:

testing a compound for the ability to inhibit PKG Iα

;

testing the compound for the ability to inhibit PKG Iβ

;

identifying the compound as a candidate drug useful in the treatment of pain if it selectively inhibits PKG Iα

relative to PKG Iβ

.

24. The method of claim 23 wherein the compound is identified as a candidate drug if the ratio of inhibition of the Iα

isoform to the Iβ

isoform is at least 2.

25. The method of claim 23 wherein the compound is identified as a candidate drug of the ratio of inhibition of the Iα

isoform to the Iβ

isoform is at least 5.

26. The method of claim 23 wherein the compound is identified as a candidate drug of the ratio of inhibition of the Iα

isoform to the Iβ

isoform is at least 10.

27. The method of claim 23 further comprising:

testing the compound for the ability to inhibit PKG II, wherein the compound is identified as a candidate drug useful in the treatment of pain if it does not inhibit PKG II.

28. The method of claim 23 further comprising:

testing the compound for the ability to inhibit cAMP-dependent protein kinase and cGMP dependent phosphodiesterase, wherein the compound isidentified as a candidate drug useful in the treatment of pain if it does not inhibit cAMP-dependent protein kinase and cGMP dependent phosphodiesterase.

29. A method for screening for drugs useful in the treatment of pain, comprising:

contacting cells with a test compound;

monitoring transcription, activity, or translation of PKG Iα

in the cells;

identifying a compound as a candidate drug if it inhibits transcription, activity, or translation of PKG Iα

.

30. The method of claim 29 wherein transcription is monitored.

31. The method of claim 29 wherein translation is monitored.

32. The method of claim 29 wherein activity of PKG Iα

is monitored.

33. The method of claim 29 further comprising:

monitoring transcription or translation of a control protein;

identifying the compound as a candidate drug if it does not inhibit transcription or translation of the control protein.

34. The method of claim 29 wherein the control protein is PKG II.

35. The method of claim 29 wherein the control protein is cAMP-dependent protein kinase.

36. The method of claim 29 wherein the control protein is a cGMP-dependent phosphodiesterase.