Enhancing excitatory activity of somatosensory cortex alleviates neuropathic pain through regulating homeostatic plasticity

Abstract

Central sensitization and network hyperexcitability of the nociceptive system is a basic mechanism of neuropathic pain. We hypothesize that development of cortical hyperexcitability underlying neuropathic pain may involve homeostatic plasticity in response to lesion-induced somatosensory deprivation and activity loss, and can be controlled by enhancing cortical activity. In a mouse model of neuropathic pain, in vivo two-photon imaging and patch clamp recording showed initial loss and subsequent recovery and enhancement of spontaneous firings of somatosensory cortical pyramidal neurons. Unilateral optogenetic stimulation of cortical pyramidal neurons both prevented and reduced pain-like behavior as detected by bilateral mechanical hypersensitivity of hindlimbs, but corpus callosotomy eliminated the analgesic effect that was ipsilateral, but not contralateral, to optogenetic stimulation, suggesting involvement of inter-hemispheric excitatory drive in this effect. Enhancing activity by focally blocking cortical GABAergic inhibition had a similar relieving effect on the pain-like behavior. Patch clamp recordings from layer V pyramidal neurons showed that optogenetic stimulation normalized cortical hyperexcitability through changing neuronal membrane properties and reducing frequency of excitatory postsynaptic events. We conclude that development of neuropathic pain involves abnormal homeostatic activity regulation of somatosensory cortex, and that enhancing cortical excitatory activity may be a novel strategy for preventing and controlling neuropathic pain.

Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury

“…We found increased neuronal spiking activity at P14 and P28 when compared with P7 ( Figure 1, G and H, and Supplemental Figure 1, B and C). In adult mice, increased spontaneous firing of corticospinal neurons is associated with maladaptive plasticity after SCI (23). We discovered that α2δ2 expression increased in adult cortico spinal neurons 7 days after a cervical 5 (C5) SCI that completely severed corticospinal axons (Figure 1, I-K, and Supplemental Figure 1D).…”

“…The expression of α2δ2 increases in corticospinal neurons during brain development and after a cervical SCI that completely transects corticospinal axons. After SCI, lack of afferent input to the somatosensory cortex causes changes in corticospinal neurons' homeostatic synaptic plasticity that lead to cortical hyperexcitability (23,32). Given that α2δ2 positively regulates synaptic transmission (33), increased α2δ2 expression likely contributes to maladaptive plasticity and detrimental alteration of neuronal function under several pathological conditions.…”

Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology, and Hebbian plasticity in the mouse hippocampus

“…Fundamental processes in the healthy hippocampus, such as sleep‐dependent memory consolidation, can induce long‐lasting enhancements the firing rate of CA1 cells (Ognjanovski, Maruyama, Lashner, Zochowski, & Aton, ). Chronic increases in neuronal activity can also influence several phenomena, such as learning and memory (Mendez et al, ), neuropathic pain processing (Xiong et al, ) and the progression of Alzheimer's disease (Yamamoto et al, ). Thus, although optogenetic excitation is a nonphysiological approach, it can be a useful tool to make homeostatic neuronal regulation—a process up to now mostly studied in cultured neurons—more amenable for in vivo studies that can investigate its relations with physiological processes in the brain.…”

Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology and Hebbian plasticity in the mouse hippocampus

“…Fundamental processes in the healthy hippocampus, such as sleep-dependent memory consolidation, can induce long-lasting enhancements the firing rate of CA1 cells (Ognjanovski et al, 2014). Chronic increases in neuronal activity can also influence several phenomena, such as learning and memory (Mendez et al, 2018), neuropathic pain processing (Xiong et al, 2017) and the progression of Alzheimer's disease (Yamamoto et al, 2015). Thus, although optogenetic excitation is a nonphysiological approach, it can be a useful tool to make homeostatic neuronal regulation a process up to now mostly studied in cultured neuronsmore amenable for in vivo studies that can investigate its relations with physiological processes in the brain.…”