The Tac4 gene-derived hemokinin-1 (HK-1) binds to the NK1 receptor, similarly to Substance
P, and plays a role in acute stress reactions and pain transmission in mice. Here
we investigated Tac4 mRNA expression in stress and pain-related regions and its involvement
in chronic restraint stress-evoked behavioral changes and pain using Tac4 gene-deleted
(Tac4-/-) mice compared to C57Bl/6 wildtypes (WT). Tac4 mRNA was detected by in situ
hybridization RNAscope technique. Touch sensitivity was assessed by esthesiometry,
cold tolerance by paw withdrawal latency from 0°C water. Anxiety was evaluated in
the light-dark box (LDB) and open field test (OFT), depression-like behavior in the
tail suspension test (TST). Adrenal and thymus weights were measured at the end of
the experiment. We found abundant Tac4 expression in the hypothalamic-pituitary-adrenal
axis, but Tac4 mRNA was also detected in the hippocampus, amygdala, somatosensory
and piriform cortices in mice, and in the frontal regions and the amygdala in humans.
In Tac4-/- mice of both sexes, stress-induced mechanical, but not cold hyperalgesia
was significantly decreased compared to WTs. Stress-induced behavioral alterations
were mild or absent in male WT animals, while significant changes of these parameters
could be detected in females. Thymus weight decrease can be observed in both sexes.
Higher baseline anxiety and depression-like behaviors were detected in male but not
in female HK-1-deficient mice, highlighting the importance of investigating both sexes
in preclinical studies. We provided the first evidence for the potent nociceptive
and stress regulating effects of HK-1 in chronic restraint stress paradigm. Identification
of its targets might open new perspectives for therapy of stress-induced pain.
