A significant portion of adolescents suffer from mental illnesses and persistent pain due to repeated stress. The components of the nervous system that link stress and pain in early life remain unclear. Prior studies in adult mice implicated the innate immune system, specifically Toll-like receptors (TLRs), as critical for inducing long-term anxiety and pain-like behaviors in social defeat stress (SDS) models. In this work, we investigated the pain and anxiety behavioral phenotypes of wild-type and TLR4-deficient juvenile mice subjected to repeated SDS and evaluated the engagement of TLR4 by measuring dimerization in the spinal cord, dorsal root ganglia, and prefrontal cortex. Male juvenile (4-week-old) mice (C57BL/6J or Tlr4^-/-) underwent six social defeat sessions with adult aggressor (CD1) mice. In WT mice, SDS promotes chronic mechanical allodynia and thermal hyperalgesia assessed via von Frey testing and the Hargreaves test, respectively. In parallel, the stressed WT mice exhibited transient anxiety-like behavior and long-lasting locomotor activity reduction in the open-field test. Tlr4^-/--stressed animals were resistant to the induction of pain-like behavior but had a remnant of anxious behavior, spending less time in the center of the arena. In WT SDS, there were concordant robust increases in TLR4 dimerization in dorsal root ganglia macrophages and spinal cord microglia, indicating TLR4 activation. These results suggest that the chronic pain phenotype and locomotor impairment induced by SDS in juvenile mice depends on TLR4 engagement evidenced by dimerization in immune cells of the dorsal root ganglia and spinal cord.

Traditionally regarded as conduits for afferent information, selected sensory axons can also act as peripheral effector units by releasing neurotransmitters and neuropeptides from their peripheral terminals. These local actions can regulate vascular tone, vascular permeability, immune-cell activity, inflammation, tissue repair, and, in specific organs, contractile function. This mini-review builds on the presentation “The Motor Function of the Sensory Axon,” delivered at the International Veterinary Emergency and Critical Care Society, held in San Diego, California, on September 4th, 2025. As part of a collection documenting scientific contributions from the meeting, it preserves and shares the key concepts presented on the peripheral effector functions of sensory axons. This review explores the efferent-like functions of sensory axons in biological processes, including neurogenic inflammation, peripheral immune modulation, and vascular control, in the context of animal physiology and disease. These actions are distinguished from the conventional sensory contribution to reflexes and motor control, which requires central synaptic processing and motor-neuron output.

A significant portion of adolescents suffer from mental illnesses and persistent pain due to repeated stress. It remains unclear which components of the nervous system are involved in the linkage between stress and pain at an early age. Prior studies in adult mice implicated the innate immune system, specifically Toll-like receptors (TLR), as critical for inducing long-term anxiety and pain-like behavior in social defeat stress (SDS) model. In this work, we investigated the pain and anxiety behavioral phenotypes of wild-type and TLR4-deficient juvenile mice subjected to repeated SDS and evaluated the engagement of TLR4 by measuring dimerization in the spinal cord, dorsal root ganglia, and prefrontal cortex. Male juvenile (4-week-old) mice (C57BL6/J or Tlr4-/-) underwent six social defeat sessions with adult CD1 aggressors. In WT mice SDS promotes chronic mechanical allodynia by von Frey testing and thermal hyperalgesia by Hargreaves test. In parallel, the stressed WT mice exhibited transient anxiety-like behavior and long-lasting locomotor activity reduction in the open-field test. Tlr4-/- stressed animals were resistant to the induction of pain-like behavior but had a remnant of anxious behavior, spending less time in the center of the arena. In WT SDS, there were concordant robust increases of TLR4 dimerization in dorsal root ganglia macrophages and spinal cord microglia, indicating activation. These results suggest that the chronic pain phenotype and locomotor impairment induced by SDS in juvenile mice depends on TLR4 engagement evidenced by dimerization in immune cells of the dorsal root ganglia and spinal cord.