ABSTRACT
Procyclidine and ethopropazine, widely used as anti-parkinsonian agents because of their anti-cholinergic action, are also known to have NMDA antagonist properties. Unlike other NMDA antagonists, these agents-because of their anti-cholinergic action-are devoid of neurotoxic side effects. In the present study, we used a sciatic nerve ligation model that produces a hyperalgesic (neuropathic pain) state in adult rats to evaluate the ability of procyclidine or ethopropazine, either alone or in combination with an alpha(2) adrenergic agonist, to ameliorate neuropathic pain. We found that both procyclidine and ethopropazine alleviated thermal hyperalgesia in a dose dependent manner; when a marginally effective dose of these agents was combined with an ineffective dose of an alpha(2) adrenergic agonist (clonidine or guanabenz), the combination therapy provided effective and long-lasting relief from neuropathic pain. In addition, the combination therapy was free from neurotoxic or behavioral side effects, and hyperactivity, a side effect associated with procyclidine monotherapy, was counteracted by clonidine.
Subject(s)
Antiparkinson Agents/pharmacology , Hyperalgesia/drug therapy , Peripheral Nervous System Diseases/drug therapy , Phenothiazines/therapeutic use , Procyclidine/therapeutic use , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Adrenergic alpha-Agonists/pharmacology , Animals , Clonidine/pharmacology , Constriction, Pathologic/complications , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Guanabenz/pharmacology , Hyperalgesia/etiology , Hyperalgesia/physiopathology , Ligation , Pain Measurement , Peripheral Nervous System Diseases/etiology , Peripheral Nervous System Diseases/physiopathology , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-2/drug effects , Sciatic NerveABSTRACT
Although T-type calcium channels were first described in sensory neurons, their function in sensory processing remains unclear. In isolated rat sensory neurons, we show that redox agents modulate T currents but not other voltage- and ligand-gated channels thought to mediate pain sensitivity. Similarly, redox agents modulate currents through Ca(v)3.2 recombinant channels. When injected into peripheral receptive fields, reducing agents, including the endogenous amino acid L-cysteine, induce thermal hyperalgesia. This hyperalgesia is blocked by the oxidizing agent 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) and the T channel antagonist mibefradil. DTNB alone and in combination with mibefradil induces thermal analgesia. Likewise, L-cysteine induces mechanical DTNB-sensitive hyperalgesia in peripheral receptive fields. These data strongly suggest a role for T channels in peripheral nociception. Redox sites on T channels in peripheral nociceptors could be important targets for agents that modify pain perception.
