The induction and maintenance of central sensitization is dependent on N -methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states

TLDR

Windup, a progressive increase in spinal cord neuron excitability following repetitive stimulation of primary afferents, is driven by temporal summation of slow synaptic potentials and is attenuated by NMDA receptor antagonists. The study examined whether NMDA receptor activation underlies primary afferent–induced hypersensitivity in flexor motoneurons and whether windup triggers central sensitization. Blocking NMDA receptors with MK‑801 or D‑CPP reduced reflex facilitation, prevented windup, and reversed established central sensitization, demonstrating that NMDA receptor activity is necessary for both the induction and maintenance of central sensitization and suggesting a therapeutic role for NMDA antagonists in post‑injury pain.

Abstract

Repetitive stimulation of small diameter primary afferent fibres produces a progressive increase in action potential discharge (windup) and a prolonged increase in the excitability of neurones in the spinal cord following the stimulus. Previous studies have demonstrated that windup is the consequence of the temporal summation of slow synaptic potentials and that the slow potentials and windup are reduced by pretreatment with N-methyl-d-aspartic acid (NMDA) antagonists. We have now examined whether primary afferent induced hypersensitivity states in flexor motoneurones are also dependent on the activation of NMDA receptors and whether windup is a possible trigger for the production of the central hypersensitivity. Both a non-competitive (MK-801) and a competitive (D-CPP) NMDA antagonist, at doses that did not modify the baseline reflex, reduced the facilitation of the flexor reflex produced by either brief electrical stimulation of the sural nerve (1 Hz for 20 sec at C-fibre strength), or by the cutaneous application of the chemical irritant mustard oil. These antagonists also prevented windup from occurring in the motoneurones. When the the MK-801 and the D-CPP were administered once a state of central facilitation had been induced by prior treatment with mustard oil, they returned the facilitated reflex to its pretreatment level. These results indicate that NMDA receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs. Because central sensitization is likely to contribute to the post-injury pain hypersenstivity states in man, these data have a bearing both on the potential role of NMDA antagonists for pre-emptive analgesia and for treating established pain states.