ArticleThe journal of headache and pain2025
Lateral habenula-rostromedial tegmental nucleus circuit mediates inflammatory pain in mice.
Article in The journal of headache and pain, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Nociceptive responses and resting-state functional connectivity of the human midbrain tegmentum.Brain structure & function · 2026Article
- Dual regulatory mechanisms of the ZI-LHb circuit in SPS&S model mice: dissociable control of aversion and anxiety through distinct downstream targets.Molecular psychiatry · 2026Article
- The Role of the Ventral Tegmental Area in Reward and Addiction: A Comprehensive Review.Neurosciences (Riyadh, Saudi Arabia) · 2026Review
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Abstract
backgroundThe monoamine system, particularly the serotonergic neurons in the dorsal raphe nucleus (DRN), associated with the synthesis and release of 5-hydroxytryptamine, is crucial for regulating pain. The lateral habenula (LHb) modulates DRN neurons by acting through GABAergic neurons located in the rostromedial tegmental nucleus (RMTg). However, the role of RMTg in mediating the LHb and regulating pain remains unclear. Thus, we aimed to assess the role of the LHb-RMTg pathway in inflammatory pain.
methodsMale C57BL/6 mice were used in the chemogenetic experiments, while male and female Vglut2-ires-cre mice were used in the optogenetic experiments; in both experiments, inflammatory pain model and control groups were established. We performed the Hargreaves and Von Frey tests to assess nociceptive behavior as well as immunohistochemistry staining after chemogenetic activation experiments. Statistical analyses were performed using a t-test, one-way analysis of variance (normally distributed data) or Kruskal-Wallis test (non-normally distributed data) and two-way analysis of variance.
resultsChemogenetic activation/inhibition of RMTg-projecting LHb excitatory neurons was sufficient to decrease or increase heat sensitivity thresholds. Additionally, inhibition of the LHb-RMTg circuit reversed the decreased heat sensitivity thresholds under inflammatory pain conditions using chemogenetic and optogenetic approaches. However, this circuit did not affect mechanical allodynia thresholds, and chemogenetic activation of the circuit decreased c-Fos immunoreactivity in the DRN.
conclusionsOur results indicate that activating glutamatergic neurons within the LHb heightens pain sensitivity by triggering GABAergic neurons in the RMTg, which in turn influences neuronal activity in the DRN. This research offers fresh perspectives on the pain mechanism, potentially revealing new therapeutic avenues for managing inflammatory pain.
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