Lateral habenula-rostromedial tegmental nucleus circuit mediates inflammatory pain in mice

The 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.

Male 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.

Chemogenetic 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.

Our 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.