FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia.

Navigating the duality of opioids' potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model.

Spinal and pontine relay pathways mediating respiratory rhythm entrainment by limb proprioceptive inputs in the neonatal rat.

The coordination of locomotion and respiration is widespread among mammals, although the underlying neural mechanisms are still only partially understood. It was previously found in neonatal rat that cyclic electrical stimulation of spinal cervical and lumbar dorsal roots (DRs) can fully entrain (1:1 coupling) spontaneous respiratory activity expressed by the isolated brainstem/spinal cord. Here, we used a variety of preparations to determine the type of spinal sensory inputs responsible for this respiratory rhythm entrainment, and to establish the extent to which limb movement-activated feedback influences the medullary respiratory networks via direct or relayed ascending pathways.

Genetic dissection of rhythmic motor networks in mice.

Simple motor behaviors such as locomotion and respiration involve rhythmic and coordinated muscle movements that are generated by central pattern generator (CPG) networks in the spinal cord and hindbrain. These CPG networks produce measurable behavioral outputs and thus represent ideal model systems for studying the operational principles that the nervous system uses to produce specific behaviors. Recent advances in our understanding of the transcriptional code that controls neuronal development have provided an entry point into identifying and targeting distinct neuronal populations that make up locomotor CPG networks in the spinal cord.

Intercostal and abdominal respiratory motoneurons in the neonatal rat spinal cord: spatiotemporal organization and responses to limb afferent stimulation.

Respiration requires the coordinated rhythmic contractions of diverse muscles to produce ventilatory movements adapted to organismal requirements. During fast locomotion, locomotory and respiratory movements are coordinated to reduce mechanical conflict between these functions. Using semi-isolated and isolated in vitro brain stem-spinal cord preparations from neonatal rats, we have characterized for the first time the respiratory patterns of all spinal intercostal and abdominal motoneurons and explored their functional relationship with limb sensory inputs.