ABSTRACT
A method is described to detect selective alpha-2 adrenergic agonists in vivo. Palpebral ptosis is induced in rats by the neuroleptic agent haloperidol (Hal), or by tetrabenazine (TBZ) methanesulfonate. Twenty minutes later, test compounds are injected, and ptosis is scored. In a separate test, muscular rigidity is induced by the opioid, fentanyl, and subsequently, test compounds are assessed for their ability to reverse muscular rigidity. Results indicate that only alpha-2 agonists reliably reverse neuroleptic-induced and TBZ-induced ptosis, as well as opioid-induced rigidity. An alpha-1 antagonist reversed only rigidity, whereas, alpha-2 antagonists and beta-agonists were generally ineffective in all tests. Therefore, the ability to reverse neuroleptic and TBZ-induced ptosis along with the ability to reverse opioid-induced muscular rigidity is a characteristic unique to alpha-2 agonists.
Subject(s)
Adrenergic alpha-Agonists/analysis , Blepharoptosis/prevention & control , Muscle Rigidity/prevention & control , Adrenergic alpha-Agonists/pharmacology , Adrenergic alpha-Antagonists/pharmacology , Animals , Blepharoptosis/chemically induced , Drug Evaluation, Preclinical/methods , Fentanyl , Haloperidol , Male , Muscle Rigidity/chemically induced , Rats , Rats, Inbred Strains , TetrabenazineABSTRACT
Compounds from several different pharmacological classes were tested for their ability to reverse the muscular rigidity induced by an intravenous dose of fentanyl that also caused loss of the righting reflex (LOR). Opioid antagonists reversed the entire syndrome--LOR and rigidity but, generally, rigidity could be reversed nonspecifically by doses of compounds that caused LOR by themselves (e.g., CNS depressants). Muscle relaxants and agonists of histamine, which appeared to be acting peripherally, were also effective. On the other hand, serotonergic drugs and dopamine agonists were not. However, dopaminergic antagonists with adrenolytic activity (i.e., chlorpromazine, haloperidol) reversed rigidity, whereas sulpiride did not. Moreover, rigidity reversed by neuroleptics could be restored by piperoxane, an alpha-2 adrenergic antagonist. In addition, clonidine and other alpha-2 agonists selectively reversed only rigidity following systemic or central administration at doses several orders of magnitude lower than other compounds tested. It is proposed that opioid-induced rigidity is reversed by inhibition of sympathoadrenal outflow which can be accomplished selectively, centrally, by alpha-2 agonists.
