Novel Target for Ameliorating Pain and Other Problems after SCI: Spontaneous Activity in Nociceptors

The purpose of the project was test the prediction that interventions that reduce the function of sodium ion channel Nav1.8 primarily expressed in nociceptive primary afferent neurons ameliorate reflex hypersensitivity and pathological pain-related motivationalcognitive alterations caused by traumatic spinal cord injury SCI. Initial findings were published in a major paper showing that antisense knockdown of Nav1.8 eliminates SCI-induced spontaneous activity SA in nociceptors, reverses mechanical and heat hypersensitivity of withdrawal reflexes, and ameliorates spontaneous pain. Extending these findings to pharmacological inhibitors of Nav1.8, intraperitoneal delivery of a selective Nav1.8 antagonist, A-803467, showed modest effects on heat hypersensitivity, mechanical hypersensitivity, spontaneous pain, and anxiety, while the nonspecific Nav1.8 antagonist, ambroxol, was ineffective. Preliminary results with intrathecal delivery of A-803467 are exciting because of the implication that ongoing Nav1.8 function in nociceptor somata with SA is required for spontaneous and evoked pain. Other findings led to a major paper showing that blockade of the cAMP-PKA signaling pathway, which enhances Nav1.8 activity, eliminates SCI-induced nociceptor SA. This project has set the stage for testing the predicted effects of selectively targeting somal rather than systemic Nav1.8 on the maintenance of pain, dysesthesia, spasticity, and anxiety after SCI.