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

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Technical Report,15 Sep 2014,14 Sep 2015

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University of Texas Health Science Center Houston

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The purpose of the project is test the hypothesis that interventions that reduce the function of a sodium ion channel, Nav1.8,that is selectively expressed in primary afferent neurons especially nociceptors ameliorate reflex hypersensitivity and pathological pain-related motivationalcognitive alterations caused by traumatic spinal cord injury SCI. The first phase of the project was accomplished, with a major paper published describing how effective antisense knockdown of Nav1.8 eliminates SCI-induced spontaneous activity in nociceptors, reverses mechanical and heat hypersensitivity of hindlimb withdrawal reflexes, and ameliorates ongoing, spontaneous pain. During the past year we have investigated effects of a selective Nav1.8 antagonist, A-803467, on heat hypersensitivity, mechanical hypersensitivity, spontaneous pain, and anxiety. We have also found that blockade of the cAMP-PKA signaling pathway, known to enhance Nav1.8 activity, eliminates SCI-induced spontaneous activity. These studies will be completed during the 6-month extension without funds. During the past two quarters we found evidence that an inexpensive but nonspecific Nav1.8 inhibitor, ambroxol, does not reduce pain-associated behavior, while the more specific antagonist, A-803467, continues to show promise not only for reducing hyperreflexia, spontaneous pain, and evoked pain, but also anxiety after SCI.

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