Effects of Protein Kinase A Activation on the Responses of Primate Spinothalamic Tract Neurons to Mechanical Stimuli

Abstract

Behavioral and anatomical studies by our group have suggested that the protein kinase A (PKA) signal transduction cascade contributes to long-term changes in nociceptive processing at the spinal cord level. In this study, we have examined the effects of activation of the PKA cascade on the responses of spinothalamic tract (STT) neurons to peripheral mechanical stimuli in anesthetized and paralyzed monkeys. PKA in the spinal cord was activated by intra-spinal infusion of forskolin, an activator of adenylate cyclase, by microdialysis. There was a consistent increase in responses to mechanical pressure and pinch stimuli in all STT cells tested when forskolin was administered. Enhanced responses remained at relatively high levels when forskolin had been washed out for 30 min. However, in most STT cells tested (65%), the responses to brushing stimuli were not obviously changed when forskolin was given. Background activity was slightly increased when forskolin was administered. An inactive isomer of forskolin,d-forskolin, did not produce significant effects on cellular activity. The sensitization of STT cells to noxious mechanical stimuli produced by forskolin could be blocked by pretreatment of the spinal cord with the PKA inhibitor, N-[2-(( p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamine (H89). The same dose of H89 did not affect the enhanced responses to mechanical stimuli produced by activation of protein kinase G by intra-spinal infusion of 8-bromo-cGMP, indicating that the effect of forskolin was selective. The present data suggest that activation of PKA can preferentially enhance the responses of STT cells to noxious mechanical stimuli without producing an increase in responses to innocuous brushing stimuli. We speculate that the PKA signal transduction cascade may contribute more to secondary mechanical hyperalgesia than to secondary mechanical allodynia.