Anesthesia and muscle relaxation with intrathecal injections of AR636 and AG489, two acylpolyamine spider toxins, in rat.

Acylpolyamine toxins are constituents isolated from many invertebrate predator venoms. These toxins are structurally novel and potent noncompetitive ligand-mediated ion channel antagonists. This study was designed to explore the sensory and motor effects of intrathecally applied acylpolyamine toxin. AR636 and AG489, acylpolyamine toxins from the spiders Argiope aurantia and Agelenopsis aperta, respectively, were injected intrathecally into rats prepared with chronic spinal catheters, and the effect on spinal function was assessed. AR636 was found to evoke a dose-dependent incidence of muscle flaccidity as well as a blockade of the agitation otherwise evoked by noxious mechanical and thermal stimuli applied to the tail or hind paws. AR636 has a calculated effective concentration (EC50) of 2 micrograms for motor inhibition and 7 micrograms for sensory inhibition. In contrast, AG489 was not found to have any effects at the highest tested dose of 50 micrograms. The precise mechanism whereby AR636 exerts its action in the rat spinal cord is not known, but in insect models, this agent is known to act as a postsynaptic, noncompetitive antagonist at a glutamate receptor and to block cholinergic-gated ion channels. Thus, this agent, a representative of the acylpolyamine toxins, has prominent effects on the sensory and motor systems of mammals, and this class of agents may be found to have potential application as spinally acting muscle relaxants and/or anesthetics.