ABSTRACT
The P2X(2/3) receptor has an important role in the nociceptive transmission. Minodronic acid is a third third-generation bisphosphonate and a potent inhibitor of bone resorption. We found that minodronic acid inhibited alpha,beta-methylene ATP-induced cation uptake with the potency higher than that of suramin in the P2X(2/3) receptor receptor-expressing cells. Other bisphosphonates did not show such activity. Subcutaneously administered (10-50 mg/kg) minodronic acid significantly inhibited the alpha,beta-methylene ATP-, acetic acid- and formalin-induced nociceptive behaviors in mice. These unique effects of minodronic acid would be beneficial for the treatment of accelerated bone turnover diseases accompanied by bone pain, including bone metastases.
Subject(s)
Analgesics, Non-Narcotic/pharmacology , Bone Density Conservation Agents/pharmacology , Diphosphonates/pharmacology , Imidazoles/pharmacology , Pain/prevention & control , Purinergic P2 Receptor Antagonists , Acetic Acid , Adenosine Triphosphate/analogs & derivatives , Analgesics, Non-Narcotic/administration & dosage , Animals , Bone Density Conservation Agents/administration & dosage , CHO Cells , Cricetinae , Cricetulus , Diphosphonates/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Formaldehyde , Imidazoles/administration & dosage , Injections, Subcutaneous , Male , Mice , Mice, Inbred ICR , Pain/chemically induced , Pain/metabolism , Pain Measurement , Receptors, Purinergic P2/genetics , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X2 , Receptors, Purinergic P2X3 , Time Factors , TransfectionABSTRACT
In some diseases in which endothelin-1 production increases, e.g. prostate cancer, endothelin-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin ET(A) receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on the nociception potentiated by endothelin-1 in a cancer inoculation-induced pain model in mice, induced by inoculation of the androgen-independent human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency (SCID) mice. No pain responses were observed in the sham-operated mice, whereas monophasic pain responses were observed in the PPC-1-inoculated mice. Endothelin-1 (1 to 10 pmol/paw) but not sarafotoxin S6c potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3 to 3 mg/kg, p.o.) significantly inhibited the endothelin-1 (10 pmol/paw)-induced potentiation of nociception in a dose-dependent manner. These results suggest that selective endothelin ET(A) receptor antagonists might relieve pain in patients with various diseases in which endothelin-1 production is increased, e.g. prostate cancer.
Subject(s)
Endothelin A Receptor Antagonists , Endothelin-1/pharmacology , Pain/drug therapy , Prostatic Neoplasms/complications , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/pharmacology , Analgesics, Non-Narcotic/therapeutic use , Animals , Atrasentan , Dose-Response Relationship, Drug , Hindlimb , Male , Mice , Mice, SCID , Pain/etiology , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Pyrrolidines/administration & dosage , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Time Factors , Viper Venoms/pharmacologyABSTRACT
We investigated the effect of YM598, a selective endothelin ETA receptor antagonist, on blood pressure (BP) in normotensive rats (NTR), spontaneously hypertensive rats (SHR) and Dahl salt-sensitive hypertensive rats (Dahl-SS). We also examined the concomitant effect of YM598 with the L-type Ca2+ channel antagonist nifedipine on BP. Single oral administration of YM598 did not affect BP in NTR and SHR. In Dahl-SS, in contrast, YM598 slightly, but not significantly, reduced BP. Concomitant administration of YM598 with nifedipine at doses inducing slight hypotension on respective single administrations resulted in a stronger hypotensive effect than single administration of either compound alone. However, the magnitude of the concomitant hypotensive effect demonstrated only a simple additive effect of the two compounds. These results indicate that YM598 did cause slight hypotensive effects in some types of hypertension. These results also indicate the possibility of additive, but not synergic, hypotensive effects on concomitant administration of ET receptor antagonist and an L-type Ca2+ channel antagonist.
Subject(s)
Blood Pressure/drug effects , Endothelin A Receptor Antagonists , Hypertension/drug therapy , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Administration, Oral , Animals , Blood Pressure/physiology , Drug Administration Schedule , Hypertension/physiopathology , Male , Rats , Rats, Inbred Dahl , Rats, Inbred SHR , Rats, Wistar , Receptor, Endothelin A/physiologyABSTRACT
In some diseases in which endothelin-1 (ET-1) production increases (e.g. prostate cancer), ET-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin-A receptor antagonist, YM598, on the nociception potentiated by ET-1 in formalin-induced and cancer inoculation-induced pain models in mice. The formalin-induced pain model was prepared by intraplantar injection of 0.7% formalin into the hind paws of ICR mice, and the cancer pain model was prepared by inoculation of the human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency mice. Formalin caused a biphasic pain response and paw edema in the mouse hind paw. ET-1 (10 pmol/paw) potentiated these responses, and single oral administration of YM598 (0.3-3 mg/kg) significantly inhibited this ET-1-induced potentiation of nociception and paw edema. ET-1 (10 pmol/paw) also potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3-3 mg/kg) significantly inhibited the ET-1-induced potentiation of nociception. These results suggest that selective endothelin-A receptor antagonists relieve pain in patients with various diseases in which ET-1 production increases (e.g. prostate cancer).