Chronic Constriction Injury Induced Long-Term Changes in Spontaneous Membrane-Potential Oscillations in Anterior Cingulate Cortical Neurons in Vivo

Abstract

Background: Neuropathic pain induction by nerve injury has been shown by in vitro studies to be accompanied by synaptic strengthening in the anterior cingulate cortex (ACC) and has been shown by pharmacological studies in vivo to be prevented by blocking N-methyl-D-aspartate (NMDA) receptor-dependent ACC plasticity. These findings indicate that ACC neurons undergo nerve injury-induced synaptic modifications and further raise a new question about neuropathic pain-associated changes in neuronal activity in the ACC in vivo, particularly spontaneous neuronal oscillations – a process believed to be fundamental for many forms of brain function. Objective: In this study, we examined the change of spontaneous membrane-potential (MP) oscillations in the ACC in vivo in a neuropathic pain animal model of chronic constriction injury (CCI), which may account for neuropathic pain development, as well as pain hypersensitivity and spontaneous pain. Study Design: Experimental trial in rats. Methods: Neuropathic pain rats were produced by CCI surgery on the common sciatic nerve. Neuropathic pain-related behaviors were accessed by evoked responses to both mechanical and thermal stimuli, as well as spontaneous pain indicated by spontaneous foot lifting. In vivo wholecell recording was performed in both control and neuropathic pain rats under anaesthesia. MP and action-potential (AP) changes of layer II/III ACC pyramidal cells were measured in current-clamp mode. The level of anaesthesia was evaluated by monitoring respiratory and heart rates in some experiments. Results: Within 7 to 14 days after CCI surgery, the frequency of MP oscillations of ACC neurons was found to be significantly higher than that in control rats. Such an increase in oscillation frequency after surgery was not due to periphery transmission via the sciatic nerve subjected to CCI surgery and was indicated to be accounted for by neuronal modifications in the central nervous system. Furthermore, this increase was found to result in a higher overall level of MP excitation as well as an increase in spontaneous AP firing. Limitations: Our findings in MP and AP changes were obtained in anaesthetized brains; this issue remains to be further examined by using whole-cell recording in awake behaving animals. Conclusions: Neuropathic pain is accompanied by the increase in rates of spontaneous oscillations of ACC neurons. This change may be critical for neuropathic pain development, as well as pain hypersensitivity and spontaneous pain in neuropathic pain animals. Key Words: Neuropathic pain, anterior cingulate cortex, spontaneous activity, neuronal oscillation, chronic constriction injury