It is demonstrated that chronic pain induces firing pattern-dependent adaptations in intrinsic excitability, with selective enhancement of responsiveness in IB neurons, which may contribute to persistent amplification of nociceptive signaling by reshaping microcircuit dynamics within the superficial dorsal horn, thereby facilitating pathological nociceptive transmission during established pain states.
Abstract
Chronic pain is associated with maladaptive plasticity within nociceptive circuits of the spinal dorsal horn (SDH). However, whether this reorganization selectively targets specific neuronal populations remains unresolved. Addressing this question has been technically challenging because reliable measurements of somatic excitability in spinal neurons are difficult to obtain under experimental pain conditions, where tissue integrity and recording stability are frequently compromised. In this comparative study, we examined neuronal excitability in two electrophysiologically distinct lamina II populations; tonic and initial burst (IB) firing neurons, under basal conditions and across three chronic pain models: complete Freund's adjuvant (CFA), spinal nerve ligation (SNL), and streptozotocin (STZ). Our results demonstrate that chronic pain induces firing pattern-dependent adaptations in intrinsic excitability, with selective enhancement of responsiveness in IB neurons. This interpretation is reinforced by principal component analysis (PCA), which partitions IB and tonic neurons into distinct electrophysiological domains. This subtype-specific plasticity may contribute to persistent amplification of nociceptive signaling by reshaping microcircuit dynamics within the superficial dorsal horn, thereby facilitating pathological nociceptive transmission during established pain states.
ABSTRACT
Spontaneous pain is a hallmark and debilitating feature of neuropathic pain, yet the mechanisms driving spontaneous pain remain poorly understood. Although abnormal spontaneous activity (SA) in primary sensory neurons has been observed after nerve injury, it remains unclear how such activity is organized across neuronal populations within the dorsal root ganglion (DRG) and how it relates to different pain components. Here, we used large-scale in vivo calcium imaging to examine spontaneous and stimulus-evoked activity in lumbar DRG neurons after spared-nerve injury (SNI). Spared-nerve injury significantly increased the incidence of single-neuron SA in DRG neurons. By combining functional imaging with retrograde labeling, we found that this activity arose not only from injured afferents (51.8%) but also from a substantial population of spared neurons (48.2%) within the same ganglion. Among spared neurons exhibiting spontaneous activity, nearly half (48.4%) showed no detectable responses to a broad panel of mechanical and thermal stimuli under our recording conditions, whereas most responsive neurons retained modality selectivity. Importantly, the incidence of single-neuron SA was positively associated with spontaneous pain-like behavior, but not with mechanical hypersensitivity, after SNI, supporting a direct link between SA of DRG neurons and spontaneous neuropathic pain. Together, these findings show that SA in the DRG is organized across both anatomical and functional dimensions, providing a framework for understanding how abnormal peripheral neuronal activity relates to spontaneous neuropathic pain.
Leo C. Guan, Jing Liu, Zhao-Li Luo et al.· Pain· 0 citations
The need for multimodal experimental approaches to more precisely define how SCS achieves analgesia is underscored, underscoring the need for multimodal experimental approaches to more precisely define how SCS achieves analgesia.
Milan Patel, Alison J Deng, Ameya V. Belamkar et al.· International Journal of Mol...· 0 citations
BACKGROUND
The nucleus accumbens (NAc) integrates affective and sensory information crucial for pain processing. While canonically viewed as a predominantly GABAergic structure, the potential existence and function of non-canonical excitatory populations remain poorly understood. We hypothesized that a distinct subpopulation of vesicular glutamate transporter 2 (VGluT2) neurons in the NAc exists and actively drives inflammatory pain and related anxiety behaviors.
METHODS
In this controlled laboratory in vivo study using male mice, we identified and characterized NAc VGluT2 neurons using patch-clamp electrophysiology. A persistent inflammatory pain model was established via intraplantar complete Freund's adjuvant (CFA) injection. To determine functionality, we used viral-mediated chemogenetics to selectively inhibit these neurons. Main outcome measures included mechanical paw withdrawal frequency (PWF), thermal paw withdrawal latency (PWL), and pain-related anxiety evaluated via the open field test (OFT) and elevated plus maze (EPM).
RESULTS
NAc VGluT2 neurons constitute a unique, non-GABAergic population, with >90% displaying intrinsic burst-firing. These neurons became significantly hyperexcitable under CFA-induced inflammatory pain conditions. Chemogenetic inhibition of NAc VGluT2 neurons successfully alleviated pain hypersensitivity. Furthermore, modulating this neuronal population bidirectionally regulated pain-related anxiety-like behaviors.
CONCLUSIONS
VGluT2 neurons in the NAc represent a functionally distinct, burst-firing population that critically gates inflammatory pain and comorbid anxiety. Inhibiting this specific microcircuit provides a novel, precise target for treating persistent pain.
Tianen Si, Zhi-Xiao Li, Ying-ying Zhang et al.· Regional anesthesia and pain...· 0 citations
