Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain.

Neuronal nicotinic receptor (NNR) agonists such as ABT 594 have been shown to be effective in a wide range of preclinical models of acute and neuropathic pain. The present study, using the NNR agonist A-85380, sought to determine if NNR agonists are acting via similar or differing mechanisms to induce anti-nociception and anti-allodynia. A systemic administration of the quaternary NNR antagonist chlorisondamine (0.4 micromol/kg, intraperitoneal (i.p.)) did not alter A-85380-induced (0.75 micromol/kg, i.p.) anti-nociception in the rat paw withdrawal model of acute thermal pain. In contrast, previous studies have demonstrated that blockade of central NNRs by prior administration of chlorisondamine (10 microg i.c.v.) prevents A-85380 induced anti-nociception indicating a predominantly central site of action of NNR agonists in relieving acute pain. In the rat spinal nerve ligation model of neuropathic pain, A-85380 induced a dose-dependent anti-allodynia (0.5-1.0 micromol/kg) that was blocked by pretreatment with mecamylamine (1 micromol/kg). Interestingly, unlike acute pain, both systemic and central administration of chlorisondamine blocked A-85380-induced anti-allodynia, an effect that was determined not to be due to a non-specific effect of chlorisondamine or to chlorisondamine crossing the blood-brain barrier. The peripheral site of action was shown not to be the primary receptive field, since A-85380 had equally potent anti-allodynic effects when it was injected into either the affected or unaffected paw. In contrast, infusion of A-85380 directly onto the L5 dorsal root ganglion on the affected side resulted in a dose-dependent and marked anti-allodynia (10-20 microg) at doses that had no effect when injected systemically. This effect was blocked by pretreatment with chlorisondamine. Together these data further support the idea that different mechanisms underlie different pain states and suggest that the effects of NNR agonists in neuropathic pain may be due in part to peripheral actions of the compounds.