Pregabalin modulation of spinal and brainstem visceral nociceptive processing

Abstract

Brainstem and spinal mechanisms mediating visceral nociception are investigated here using electrophysiology and immunohistochemistry techniques in a model of acute visceral pain. Colorectal distension (CRD) produced graded visceromotor responses (VMR) in normal rats, and these were facilitated by intracolonic mustard oil (MO) that generated acute visceral hyperalgesia. The neuropathic pain drug pregabalin (PGB) is thought to have state-dependent effects in attenuating neuropathic, but not acute somatic pain, likely by impairing calcium-channel trafficking. We found that systemic PGB produced antinociceptive effects on CRD-evoked VMRs in naïve rats lacking pathophysiology and in MO-pretreated rats. Systemic PGB also significantly reduced Fos labelling in lumbosacral spinal cords of rats given noxious repetitive CRD; however, PGB did not alter this measure of neural activity in the brainstem. Differential brainstem processing of noxious somatic and visceral stimuli may underlie the unique lack of state-dependent actions of PGB in this visceral pain model. Single-unit recordings in the rostral ventromedial medulla (RVM) verify that brainstem processing of somatic and visceral stimuli differs. The effects of CRD on RVM cells classed as ON, OFF, or NEUTRAL were independent of their somatic responses, with surprising changes in RVM cell activity to innocuous visceral stimulation. PGB also markedly reduced the visceral responses of RVM ON-cells to noxious CRD. These results illustrate clear differences in the central processing of visceral and somatic stimuli, yet a common role for descending modulation by brainstem activity in mediating evoked pain measures.