Summary Primary nociceptors relay painful touch information from the periphery to the spinal cord. While it is established that signals generated by the receptor tyrosine kinases TrkA and Ret coordinate the development of distinct nociceptive circuits, mechanisms modulating TrkA or Ret pathways in developing nociceptors are unknown. We have identified tumor necrosis factor receptor 1 (TNFR1) as a critical modifier of TrkA and Ret signaling in peptidergic and non-peptidergic nociceptors. In particular, TrkA+ peptidergic nociceptors require TNFα-TNFR1 forward signaling to suppress NGF-mediated neurite growth, survival, excitability, and differentiation. Conversely, TNFR1-TNFα reverse signaling augments the neurite growth and excitability of Ret+ non-peptidergic nociceptors. The developmental and functional nociceptive defects associated with loss of TNFR1 signaling manifest behaviorally as lower pain thresholds caused by increased sensitivity to NGF. Thus, TNFR1 exerts a dual role in nociceptor information processing by suppressing TrkA and enhancing Ret signaling in peptidergic and non-peptidergic nociceptors, respectively.

1. Stable intracellular recordings were obtained from neurons (n = 62) in the L6-S1 deep dorsal horn of the spinal cord in pentobarbital-sodium-anesthetized, intact rats (n = 26). All neurons responded to natural mechanical stimuli and/or electrical stimulation of peripheral afferents. 2. Intracellular penetrations were maintained for 30 min-2 h. Action potentials occurred spontaneously in most neurons (n = 50) and could be evoked in the remainder (n = 12) by depolarizing current passage. Mean resting membrane potential was -60.9 mV, mean action potential height amplitude was 75.2 mV, mean half-width of the action potentials was 0.33 ms, mean input resistance was 38 M omega, and mean time constant was 9.1 ms. 3. Action potentials were followed by afterpotentials made up of at least three components; a fast afterhyperpolarization (fAHP), a slow afterhyperpolarization (sAHP), and an afterdepolarization (ADP). Most neurons (n = 40) exhibited all three afterpotentials, although some displayed only a fAHP and an ADP (n = 10) or a fAHP and a sAHP (n = 12). The durations and magnitudes of the afterpotentials varied widely among neurons. 4. Steady-state current-voltage relations were investigated in 14 neurons with depolarizing and hyperpolarizing current pulses. Of these 14 neurons, 5 exhibited inward rectification, 3 had outward rectification, and the remaining 6 showed a predominantly linear change of membrane potential to current injection. In addition, several neurons (n = 9) exhibited a postinhibitory rebound that was sometimes (n = 4) accompanied by a "sag" in voltage during the preceding hyperpolarizing current step. 5. Four patterns of spike frequency adaptation occurred during step depolarizing current passage. The firing of most neurons gradually decreased with a simple, approximately exponential time course (n = 21), in some neurons it decreased with both a fast and a slow time course (n = 8), in several it incremented in rate (n = 3), and one neuron showed a complex combination of multiple decrementing and incrementing adaptations. Time constants, magnitude of adaptation, and the slopes of the steady-state current-voltage relation varied widely. 6. Oscillations in membrane potential and firing rate occurred in three neurons. The oscillations arose from endogenous mechanisms in at least one neuron because manipulation of membrane potentials altered the frequency of oscillation; a depolarizing current increased the period of oscillation and eventually produced tonic firing, and a hyperpolarizing current increased the frequency of oscillation and eventually terminated firing. 7. The results demonstrate that neurons in the L6-S1 region of the dorsal horn exhibit a diversity of cellular mechanisms that may significantly modulate normal somatosensory and visceral input.

The input-output properties of interneurons mediating spinal reflexes were investigated by extracellularly recording the response of interneurons to excitation from muscle receptors in the ankle extensor muscles of decerebrated, spinal cats. A population ofinterneurons in the intermediate region ofthe spinal cord is potently excited by increases in muscle force. Unlike the discharge of Golgi tendon organs, which accurately encodes moment-to-moment variations in the force of a single muscle, the discharge of these interneurons depends in a dynamic and usually nonlinear way on the force in several muscles. Powerful input from unidentified mechanoreceptors in muscle, presumably free nerve endings, is at least partly responsible for these properties. These force-sensitive interneurons are more likely to mediate clasp knife-type inhibition than simple negative force feedback.

The potential contributions of cervical spinal interneurons to the neural control of respiration have been investigated by extracellularly recording the patterns of activity of neurons in the C4-C6 spinal cord during fictive respiration in the fluorocarbon-perfused, adult guinea pig. Two types of neurons were recorded: respiratory-modulated neurons, whose activity was modulated with respiration, and phrenic-driven neurons, which were excited by electrical stimulation of the phrenic nerve. Respiratory-modulated neurons (n = 20) could be divided into inspiratory, expiratory, and phase-spanning neurons, based on their patterns of activity during fictive respiration. Respiratory-modulated neurons showed varying dependencies on the type of breathing; during spontaneous augmented breaths, one-half exhibited patterns of activity that were significantly different to those seen during normal, fictive respiration, whereas the other half of the respiratory-modulated neurons showed similar patterns of activity during both normal and augmented breaths. Phrenic-driven neurons (n = 22) could be divided into short-latency (7-12 ms), moderate-latency (12-25 ms), and inhibited neurons, but were only occasionally and weakly modulated with respiration. The results suggest that respiratory-modulated C4-C6 spinal neurons may contribute to the neural control of respiration, with different subpopulations specialized for different types of respiratory tasks, and that phrenic-driven neurons may be interposed in sensory or reflex pathways, such as the spinothalamic tract or phrenic-to-phrenic inhibitory reflex.

1. The goal of this study was to characterize the clasp-knife reflex by the use of stretch and isometric contraction of ankle extensor and flexor muscles in decerebrated cats with bilateral dorsal hemisections of their spinal cords at segment T12. 2. Stretch of an extensor muscle evoked inhibition in both homonymous and synergistic extensor muscles. The similarities between homonymous and synergistic inhibition suggest that similar neural mechanisms were responsible. 3. Homonymous and synergistic clasp-knife inhibition showed several characteristic features: 1) inhibition was evoked only by large stretches that produced significant muscle force. Short stretches that did not produce large forces evoked only excitation; 2) the magnitude of clasp-knife inhibition increased with increasing initial motor output, as reflected in the level of rectified EMG; 3) the time course of reflex inhibition evoked by ramp-and-hold stretch was characterized by segmentation of EMG during ramp stretch, dynamic overshoot of inhibition at the end-of-ramp stretch, and slow but usually complete decay of inhibition during maintained stretch; 4) inhibition persisted beyond the termination of stretch, and 5) inhibition showed adaptation to repeated stretch. 4. Isometric contraction of the soleus or medial gastrocnemius, produced by electrical stimulation of the muscle nerve, also evoked powerful synergistic-reflex inhibition via similar mechanisms as stretch-evoked, clasp-knife inhibition. Stretch evoked a greater degree of inhibition than did contraction, indicating that receptors responsive to both stretch and contraction contribute to clasp-knife inhibition. 5. The reflex effects produced by stretching the soleus or medial gastrocnemius were not confined to the homonymous and close synergistic muscles. Extensor muscles were inhibited and flexor muscles were excited throughout the hindlimb, which paralleled the pattern of a flexion-withdrawal reflex evoked by cutaneous stimulation. 6. Stretch of a flexor muscle, the tibialis anterior, evoked the same spatial pattern and time course of reflex action as stretch of an extensor muscle--inhibition of extensor muscles and excitation of flexor muscles throughout the hindlimb, including homonymous excitation of the tibialis anterior. 7. We conclude that neither Golgi tendon organs nor secondary spindle afferents are likely to contribute significantly to clasp-knife inhibition because their responses to stretch and isometric contraction differ from the reflex actions evoked by stretch and contraction.(ABSTRACT TRUNCATED AT 400 WORDS)