Method of restoring analgesic efficacy of alpha2-adrenoceptor agonists in neuropathic pain treatment

Abstract

Provided are a pharmaceutical composition including: an alpha 2 (α2)-adrenoceptor agonist; a regulator of G-protein signaling (RGS) inhibitor, an endocytosis inhibitor, or a combination thereof; and a pharmaceutically acceptable salt, and a method of relieving pain of a subject, the method including administering the pharmaceutical composition to a subject.

1 . A pharmaceutical composition for relieving pain, the composition comprising:
 an alpha 2 (α2)-adrenoceptor agonist;   a regulator of G-protein signaling (RGS) inhibitor, an endocytosis inhibitor, or a combination thereof; and   a pharmaceutically acceptable salt.   
     
     
         2 . The composition of  claim 1 , wherein the α2-adrenoceptor agonist is 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tiamenidine, tizanidine, tolonidine, xylazine, xylometazoline, or a combination thereof. 
     
     
         3 . The composition of  claim 1 , wherein the RGS is RGS4 or RGS8. 
     
     
         4 . The composition of  claim 1 , wherein the RGS inhibitor is CCG-50014, CCG-2046, CCG-63802, CCG-4986, CCG-203769, or a combination thereof. 
     
     
         5 . The composition of  claim 1 , wherein the endocytosis inhibitor is dynasore, dynole, methyl-beta-cyclodextrin, Bis-T, MitMAB, OctMAB, pitstop-1, pitstop-2, chlorpromazine, chloroquine, or a combination thereof. 
     
     
         6 . The composition of  claim 1 , wherein the pain is inflammatory pain, visceral pain, somatic pain, superficial somatic pain, deep somatic pain, cancer pain, somatic referred pain, neuropathic pain, or a combination thereof. 
     
     
         7 . The composition of  claim 6 , wherein the neuropathic pain is chronic neuropathic pain. 
     
     
         8 . The composition of  claim 1 , wherein the composition is for improving a side effect of the α2-adrenoceptor agonist. 
     
     
         9 . The composition of  claim 8 , wherein the side effect is low blood pressure or low mobility. 
     
     
         10 . The composition of  claim 1 , wherein the α2-adrenoceptor agonist is clonidine, and an amount of clonidine is about 0.45 mg or less. 
     
     
         11 . The composition of  claim 1 , wherein the α2-adrenoceptor agonist is clonidine, and about 0.2 mg or less of clonidine is contained therein. 
     
     
         12 . A method of relieving pain of a subject, the method comprising:
 administering the pharmaceutical composition of  claim 1  to a subject.   
     
     
         13 . The method of  claim 12 , wherein the administering of the pharmaceutical composition is performed by simultaneously, individually, or sequentially administering: an alpha 2 (α2) adrenoceptor agonist; and a regulator of G-protein signaling (RGS) inhibitor, an endocytosis inhibitor, or a combination thereof. 
     
     
         14 . The method of  claim 12 , wherein the method is for improving a side effect of the α2-adrenoceptor agonist. 
     
     
         15 . The method of  claim 12 , wherein the α2-adrenoceptor agonist is administered in a dose not causing low blood pressure. 
     
     
         16 . The method of  claim 15 , wherein, when the α2-adrenoceptor agonist in the pharmaceutical composition is Clonidine, the dose thereof not causing low blood pressure is about 0.45 mg or less. 
     
     
         17 . The method of  claim 15 , wherein, when the α2-adrenoceptor agonist in the pharmaceutical composition is dexmedetomidine, the dose thereof not causing low blood pressure is about 10 μg/kg or less. 
     
     
         18 . The method of  claim 12 , wherein the subject is a human. 
     
     
         19 . The composition of  claim 1 , wherein the α2-adrenoceptor agonist is dexmedetomidine, and a dose of dexmedetomidine is about 10 μg/kg or less.