ABSTRACT
Phα1ß toxin is a peptide purified from the venom of the armed spider Phoneutria nigriventer, with markedly antinociceptive action in models of acute and persistent pain in rats. Similarly to ziconotide, its analgesic action is related to inhibition of high voltage activated calcium channels with more selectivity for N-type. In this study we evaluated the effect of Phα1ß when injected peripherally or intrathecally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of Phα1ß on Ca²âº transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor. Intraplantar or intrathecal administered Phα1ß reduced both nocifensive behavior and mechanical hypersensitivity induced by capsaicin similarly to that observed with SB366791, a specific TRPV1 antagonist. Peripheral nifedipine and mibefradil did also decrease nociceptive behavior induced by intraplantar capsaicin. In contrast, ω-conotoxin MVIIA (a selective N-type Ca²âº channel blocker) was effective only when administered intrathecally. Phα1ß, MVIIA and SB366791 inhibited, with similar potency, the capsaicin-induced Ca²âº transients in DRG neurons. The simultaneous administration of Phα1ß and SB366791 inhibited the capsaicin-induced Ca²âº transients that were additive suggesting that they act through different targets. Moreover, Phα1ß did not inhibit capsaicin-activated currents in patch-clamp recordings of HEK293 cells that expressed TRPV1 receptors. Our results show that Phα1ß may be effective as a therapeutic strategy for pain and this effect is not related to the inhibition of TRPV1 receptors.
Subject(s)
Analgesics, Non-Narcotic/therapeutic use , Disease Models, Animal , Ganglia, Spinal/drug effects , Membrane Transport Modulators/therapeutic use , Neuralgia/drug therapy , Neurons/drug effects , Spider Venoms/therapeutic use , Analgesics, Non-Narcotic/pharmacology , Animals , Behavior, Animal/drug effects , Calcium Signaling/drug effects , Capsaicin , Cells, Cultured , Ganglia, Spinal/cytology , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , HEK293 Cells , Humans , Insect Proteins/pharmacology , Insect Proteins/therapeutic use , Male , Membrane Transport Modulators/pharmacology , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neuralgia/metabolism , Neuralgia/pathology , Neurons/cytology , Neurons/metabolism , Neurons/pathology , Peptides/pharmacology , Peptides/therapeutic use , Rats , Rats, Wistar , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Spider Venoms/pharmacology , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolismABSTRACT
Signaling pathways play important roles in the coordination and integration of a myriad cellular functions. Because of widespread interest in the dopaminergic pathways, the protein dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein with molecular weight of 32 kDa, known by the acronym DARPP-32, occupies a central role in the biology of dopaminoceptive neurons in the central and peripheral nervous system (PNS). Its involvement has been demonstrated in many neural phenomena, including physiologic and pathologic neuroplasticity to drug effects and cognition. However, DARPP-32 has also been identified in non-neuronal tissues and its level of expression has been associated with the malignant level of some types of cancer, via modulation of cell survival and differentiation. This review considers some of these apparently compartmentalized functions of DARPP-32 and its potential as a therapeutic target.
