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Temporal Multi-Omic Exploration of the Ventral Tegmental Area in Chronic Pain and Passive Coping Behaviors

ABSTRACT: The comorbidity of chronic pain and mood disorders represents a significant clinical challenge, yet the underlying neurobiological mechanisms within key brain regions like the ventral tegmental area (VTA) remain poorly understood. To address this, a multidisciplinary approach was employed, combining proteomics, phosphoproteomics, and lipidomics with behavioral and immunohistochemical analyses in a mouse model of neuropathic pain induced by partial sciatic nerve ligation (pSNL). The data reveal a temporal shift in the VTA proteome, progressing from an early (1-week) signature of metabolic reallocation and increased protein synthesis to a late (4-week) state of excitotoxic stress, characterized by impaired energy metabolism, autophagy, and cytoskeletal breakdown. This late maladaptive state was associated with two convergent mechanisms promoting hyperexcitability: sex-specific remodeling of Kv7 potassium channel subunit expression in VTA dopamine neurons and a deficit in the endocannabinoid 2-arachidonoylglycerol (2-AG). The development of passive coping behavior, a correlate of negative affect, was associated with these molecular changes. Notably, pharmacological restoration of 2-AG signaling or potentiation of Kv7 channel function reversed the pain-induced passive coping behavior. These findings delineate a progressive molecular pathology in the VTA and identify the 2-AG and Kv7 systems as therapeutically-relevant nodes linking chronic pain to the development of these behavioral states.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Paul Langlais

LAB HEAD: Arthur C.

PROVIDER: PXD072701 | Pride | 2026-04-30

REPOSITORIES: Pride

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			Action	DRS
	20230825_C3P0_4814_1.raw	Raw
	20230825_C3P0_4814_1.raw__F007781_.mzid	Mzid
	20230825_C3P0_4814_1.raw__F007781_.mzid_20230825_C3P0_4814_1.raw__F007781_.MGF	Mzid
	20230825_C3P0_4814_15.raw	Raw
	20230825_C3P0_4814_15.raw__F007783_.mzid	Mzid

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Project description:Background: As pain persists, it is often accompanied by the development of negative emotional states, such as depression. Approximately 50%-85% of patients with chronic pain experience depressive symptoms. Ventral tegmental area (VTA) γ--aminobutyric acid (GABA) neurons play a crucial role in regulating emotions. VTA GABA neurons can be mainly classified into those expressing somatostatin (SST) and parvalbumin (PV) neurons. The subtypes of VTA GABA neurons exhibit significant heterogeneity, but it remains unclear whether these subtypes mediate different functions in the development of chronic pain and depression. Inward rectifying potassium channel 4.1 (Kir4.1) is an important potassium channel mainly expressed in astrocytes and plays an important role in regulating neural activity. In lipopolysaccharide (LPS)-induced depression, Kir4.1 in lateral habenula (LHb) was upregulated. Lys05 (an inhibitor of Kir4.1) reversed the Kir4.1-driven depression-like phenotype. However, there was no study has reported the changes of Kir4.1 in chronic pain-induced depression or verified the therapeutic effects of Lys05 on it. Methods: We established chronic constriction injury (CCI) model to induce chronic pain in mice, and used the sugar preference test (SPT), tail suspension test (TST), and open field test (OFT) to detect depressive behavior in mice. Lys05 was injected to investigate the effect of Kir4.1 inhibitors on depression caused by chronic neuropathic pain. The adeno-associated virus (AAV) was designed to knockdown or overexpress the expression of Kir4.1 in VTA astrocytes. Using optogenetic manipulations and transgenic mice, specific activation of VTA GABASST neurons or VTA GABAPV neurons was used to explore which types of VTA GABA neurons Kir4.1 has effects on. Patch-clamp recording was applied to explore the effects of Kir4.1 on the excitability of different types of VTA neurons. Results: Lys05 could reverse the depressive behaviors induced by LPS. In detail, mice treated with 10 mg/kg Lys05 showed increased sucrose preference, decreased immobility durations in TST and increased percent center time in OFT. However, Lys05 didn’t show any specific response to depression behavior in CCI-induced depression mice. Then we found Kir4.1 expression decreased in VTA and LHb of CCI-induced depression mice. Next, we found knockdown of Kir4.1 in the VTA resulted mice became depression but with no hyperalgesia. Correspondingly, overexpress Kir4.1 in VTA astrocytes could reverse the chronic pain-induced depression like states. In the patch clamp, when knocked down Kir4.1 in VTA astrocytes, the excitability of dopamine neurons decreased, GABASST neurons increased, but GABAPV neurons did not change significantly. Specifically excitable VTA GABASST neurons could cause depression in mice, while excitable GABAPV neurons did not. Conclusion: Chronic pain decreases the expression of Kir4.1 in VTA astrocytes, which activates GABASST neurons and in turns inhibits DA neurons, then leads depression.

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Temporal Multi-Omic Exploration of the Ventral Tegmental Area in Chronic Pain and Passive Coping Behaviors

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