International immunopharmacology · 2025
Tyrosine hydroxylase-expressing neurons in the paraventricular nucleus of the hypothalamus regulate peripheral leukocytes during inflammatory pain.
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Li Xiaohui, Jia Yifu, Li Yang, Peng Minjing, Xiong Mengyuan, Zhu Qinghong, Gao Yan, Ke Changbin
Аннотация
BACKGROUND: People suffering from pain are more susceptible to infection due to the pain-induced alterations of immune function. The release of glucocorticoids (GCs) via the activation of the hypothalamus-pituitary-adrenal (HPA) axis has been considered as a major explanation for regulating glucose and energy mobilization, and immune function in response to stress. However, whether the abnormal immune function induced by inflammatory pain is associated with the excess release of corticosterone remains elusive. Central and peripheral neuronal circuits and immune organ innervation have been shown to be involved in modulating immune function. Whether the specific neurons regulating corticosterone release in addition to the HPA axis is unknown.
OBJECTIVE: To investigate the specific neurons involved in inflammatory pain model to regulate peripheral leukocytes.
METHODS: The alterations of leukocytes and lymphocytes were determined with an automatic hematology analyzer in inflammatory pain induced by complete Freund's adjuvant (CFA). The kinetics of corticosterone, adrenocorticotrophic hormone (ACTH), and norepinephrine (NE) levels were determined by enzyme linked immunosorbent assay (ELISA) after the establishment of an experimental inflammatory pain model. The dual viral retrograde tracing technique was combined with immunofluorescence staining to identify the specific neurons involved in the connection between the adrenal gland and brain region. The excitability of tyrosine hydroxylase (TH)-expressing neurons was investigated by c-Fos staining and calcium imaging analysis. The alterations of leukocytes and the release of corticosterone were observed after the excitability of TH-expressing neurons was selectively silenced using chemogenetic.
RESULTS: CFA-induced inflammatory pain caused severe leukopenia and lymphopenia that were associated to the increased corticosterone levels. Viral retrograde tracing from the adrenal gland showed that TH-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) participated in the regulation of corticosterone release, but did not result from the activation of the HPA axis. The excitability of TH neurons in the PVN were enhanced under inflammatory pain conditions. The selective inhibition of TH-expressing neuronal excitability via a designer receptor exclusively activated by designer drugs (DREADD)-hM4D(Gi) significantly reduced the release of peripheral corticosterone and ameliorated leukopenia and lymphopenia.
CONCLUSIONS: These results revealed that TH-expressing neurons in the PVN were connected with the corticosterone released from the adrenal gland, which eventually drove pain-induced leukocyte mobilization.
OBJECTIVE: To investigate the specific neurons involved in inflammatory pain model to regulate peripheral leukocytes.
METHODS: The alterations of leukocytes and lymphocytes were determined with an automatic hematology analyzer in inflammatory pain induced by complete Freund's adjuvant (CFA). The kinetics of corticosterone, adrenocorticotrophic hormone (ACTH), and norepinephrine (NE) levels were determined by enzyme linked immunosorbent assay (ELISA) after the establishment of an experimental inflammatory pain model. The dual viral retrograde tracing technique was combined with immunofluorescence staining to identify the specific neurons involved in the connection between the adrenal gland and brain region. The excitability of tyrosine hydroxylase (TH)-expressing neurons was investigated by c-Fos staining and calcium imaging analysis. The alterations of leukocytes and the release of corticosterone were observed after the excitability of TH-expressing neurons was selectively silenced using chemogenetic.
RESULTS: CFA-induced inflammatory pain caused severe leukopenia and lymphopenia that were associated to the increased corticosterone levels. Viral retrograde tracing from the adrenal gland showed that TH-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) participated in the regulation of corticosterone release, but did not result from the activation of the HPA axis. The excitability of TH neurons in the PVN were enhanced under inflammatory pain conditions. The selective inhibition of TH-expressing neuronal excitability via a designer receptor exclusively activated by designer drugs (DREADD)-hM4D(Gi) significantly reduced the release of peripheral corticosterone and ameliorated leukopenia and lymphopenia.
CONCLUSIONS: These results revealed that TH-expressing neurons in the PVN were connected with the corticosterone released from the adrenal gland, which eventually drove pain-induced leukocyte mobilization.