Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state

Abstract

PurposeVentral tegmental area (VTA) dopamine system plays an important role in depression and is also involved in pain experience. In this study, we investigated the VTA dopaminergic (DA) neuron firing and local field potential (LFP) in pain-related depression, and we try to explore the underlying relationship between pain and depression.Materials and methodsWe used neuropathic pain model [spare nerve injury (SNI)] to induce pain-related depression. The Dixon up–down method was used to test mechanical hypersensitivity. Behavioral changes like open field test, sucrose preference test, and forced swim test were used to test depression-like behaviors. Gabapentin (GBP) was used to explore the chronic analgesic treatment that could reverse pain-related depression. To investigate the in vivo variations of VTA DA neuron firing and LFP, multichannel acquisition processor system was used.ResultsWe used SNI to induce depression-like behaviors. Repeated GBP treatment reversed these behaviors after 14 days of injection. An in vivo electrophysiological analysis of the firing characteristics of VTA DA neurons and LFP revealed that SNI increased the firing rate of DA neurons, but not the burst firing activity. Surprisingly, chronic GBP reversed the firing rate of DA neurons and reduced the burst firing activity. Moreover, SNI increased the LFP power in delta and theta oscillation and decreased it in beta oscillation. Repeated administration of GBP significantly suppressed theta oscillation. Above all, chronic GBP altered these characteristics to reverse depression-like behaviors.ConclusionThe present study confirmed that the tonic firing activity of VTA DA neurons, but not the burst firing activity, was the key factor in peripheral neuropathy–induced depression. Chronic GBP regulated the firing pattern of DA neurons and decreased theta oscillation in VTA to treat pain-related depression. This variation tendency of electrophysiological characteristics of VTA DA neurons and theta oscillation in VTA might represent an attempt to cope with pain-related negative mood disorder.

Pulsed Radiofrequency on Dorsal Root Ganglion Improves Neuropathic Pain-induced Depression in SNI Rats by Regulating Hippocampal BDNF and Neuroinflammation via Spinal IRF8 Inactivation

“…We observed that the 50% PWT and sucrose preference percentage were signi cantly decreased, while the immobility time of FST was signi cantly increased due to SNI. Our results reproduced the previous ndings that animals with PNI could display anhedonia and behavioral despair [34,35]. In the current study, PRF-DRG therapy resulted in a dramatic increase in 50% PWT in rats from day 8 to day 42 after SNI, which was consistent with the results reported by Liu et al [36].…”

Formalin-induced and neuropathic pain altered time estimation in a temporal bisection task in rats

“…It has been demonstrated that partial sciatic nerve ligation induced neuropathic pain significantly decreased the proportion of activated DA neurons in the lateral VTA 63 . However, Fu et al ., found that that spared nerve injury (SNI) can significantly increase the firing rate of VTA DA neurons 64 . These opposite effects may be due to the heterogeneity of DA neurons in VTA and the opposite functions of medial and lateral neurons in VTA 65 .…”

“…S1). Some studies have observed depressive symptoms at 2 weeks 77 or 4–6 weeks 64 after spare nerve injury (SNI) surgery in rats. These studies used the same species of animal as our present study, but a different neuropathic pain model.…”

How to study anxiety and depression in rodent models of chronic pain?

“…Despite all these protocol variations, the majority of reported studies could asses a presence of anhedonia from one week (Fang, Zhan, et al, 2019; Goffer et al, 2013; Martinez‐Navarro et al, 2019; Wu et al, 2018; Xu et al, 2017; Zhu et al, 2017) to 10–11 weeks (Fang, Xu, Lin, & Liu, 2019; Fu et al, 2018; Thompson et al, 2018; Wu et al, 2014) after neuropathic pain induction (see also Figures 5 and 6 and Table 1). However, this time window depends on the considered model.…”