Windup of Nociceptive Flexion Reflex Depends on Synaptic and Intrinsic Properties of Dorsal Horn Neurons in Adult Rats

Abstract

Windup, a progressive increase in spinal response to repetitive stimulations of nociceptive peripheral fibers, is a useful model to study central sensitization to pain. Windup is expressed by neurons in both the dorsal and ventral horn of the spinal cord. In juvenile rats, it has been demonstrated both in vivo and in vitro that windup depends on calcium-dependent intrinsic properties and their modulation by synaptic components. However, the involvement of these two components in the adults remains controversial. In the present study, by means of electromyographic and extracellular recordings, we show that windup in adults, in vivo, depends on a synaptic balance between excitatory N-methyl-D-aspartate (NMDA) receptors and inhibitory glycinergic receptors. We also demonstrate the involvement of L-type calcium channels in both the dorsal and ventral horn of the spinal cord. These results indicate that windup in adults is similar to juvenile rats and that windup properties are the same regardless of the spinal network, i.e., sensory or motor.

Neurodynamic Treatment Promotes Mechanical Pain Modulation in Sensory Neurons and Nerve Regeneration in Rats

“…In addition, it was possible to determine the nerve mechanical irritability by recording the number of paw withdrawals to repeated high-frequency nerve tensions, which showed significantly increased irritability of the neural tissue to mechanical stress only in the not treated group. At the time this test was administered, sensory recovery for touch and pain was restored for all groups ( Figure 2 and Figure 3 ), and the test frequency, five times higher than treatment, was able to elicit temporal summation [ 56 , 57 ]. These data confirm that NDT can promote pain descending modulation effects as confirmed by an increased expression of the µ-opioid receptor in the DRG and k-opioid receptor in the periaqueductal grey detected in neuropathic pain models of rats treated with NDT protocols [ 59 , 79 ].…”

“…Despite the encouraging data obtained on nerve regeneration and mechanical pain modulation processes induced by the NDT also observed in other experiments on rat models of neuropathic pain [ 59 , 78 , 80 ], it is worth be reminded of the neuropathic pain complexity. This is a phenomenon involving multiple-level changes in the peripheral and central nervous systems affecting the immune and endocrine systems [ 56 , 57 , 83 , 84 , 85 ]. Our assessments were limited at exploring the mechanisms of the stimuli-dependent phenomena of MA and hyperalgesia, but neuropathic pain is also responsible for other disabling conditions such as persistent pain and nocturnal pain.…”

“…Twenty-two days after the injury, mechanical nerve irritability was assessed at the injured side by recording the number of paw withdrawals during 30 consecutive nerve tensions administered until resistance was perceived by the clinician. Tensions were administered at 0.5 Hz frequency (five times higher rate than treatment protocols; 0.5/s tension/release) able to induce a windup or temporal summation phenomenon, consisting of transiently increased responsiveness of spinal neurons to nociceptive peripheral fibres repeated stimulations [ 56 , 57 ]. This test assessed the performance of the pain descending inhibitory system and central sensitization to pain, processes that NDT possibly affects as reported in the literature [ 58 , 59 ].…”

A Minimally Invasive Method for Observing Wind-Up of Flexion Reflex in Humans: Comparison of Electrical and Magnetic Stimulation

“…One important aspect of wind-up is the involvement of N -methyl- D -aspartate (NMDA) receptors in dorsal horn neurons ( Herrero et al, 2000 ; Fossat et al, 2007 ; Aby et al, 2019 ) and wind-up of the flexion reflex in humans is indeed inhibited by the NMDA receptor antagonist ( Arendt-Nielsen et al, 1995 ; Guirimand et al, 2000 ). Therefore, quantification of wind-up in individual subjects would be useful for evaluation of NMDA receptor function and chronic pain diagnosis or psychiatric disorders.…”