PKCγ receptor mediates visceral nociception and hyperalgesia following exposure to PTSD-like stress in the spinal cord of rats

BACKGROUND: Clinical studies indicate that patients with post-traumatic stress disorder (PTSD) frequently share comorbidity with numerous chronic pain conditions. However, the sustained effects of PTSD-like stress over time on visceral nociception and hyperalgesia have been rarely studied, and the underlying mechanisms of stress-induced modulation of visceral hyperalgesia remain elusive. The purpose of this study was to investigate the characterization of visceral nociception and hyperalgesia over time in rats exposed to PTSD-like stress, and to explore the potential role of protein kinase C gamma (PKCγ) in mediating visceral hyperalgesia following exposure to PTSD-like stress. RESULTS: On day 1, the rats exposed to single-prolonged stress (SPS, an established animal model for PTSD) exhibited an analgesic response and its visceromotor response (VMR) to graded colorectal distention (CRD) at 40 and 60 mmHg was reduced compared with the control group (all P < 0.05). On day 6, the VMR returned to the baseline value. However, as early as 7 days after SPS, VMR dramatically increased compared with its baseline value and that in the controls (all P < 0.001) and this increase persisted for 28 days, with the peak on day 9. Abdominal withdrawal reflex (AWR) scores were higher in SPS rats than in controls on days 7, 9, 14, 21 and 28 (all P < 0.001). Intrathecal administration of GF109203X (an inhibitor of PKC gamma), attenuated the SPS-induced increase in both VMR and AWR scores on days 7, 14, 21 and 28 (all P < 0.05). PKCγ protein expression determined by immunofluorescence was reduced in the spinal cord within 3 days after the exposure to SPS (P < 0.01), which returned to normal levels between days 4 and 6, and significantly increased from day 7, and this increase was maintained on days 14, 21, and 28 (all P < 0.001), with the peak on day 9. In addition, Western blotting showed a consistent trend in the changes of PKCγ protein expression. CONCLUSIONS: The modified SPS alters visceral sensitivity to CRD, and contributes to the maintenance of visceral hyperalgesia, which is associated with enhanced PKCγ expression in the spinal cord. Functional blockade of the PKCγ receptors attenuates SPS-induced visceral hyperalgesia. Thus, the present study identifies a specific molecular mechanism for visceral hyperalgesia which may pave the way for novel therapeutic strategies for PTSD-like conditions.