Experimental nerve injury : induced pain : mechanisms and modulation

Abstract

Chronic nerve injury-induced pain presents a therapeutic challenge since such pain is often resistant to conventional analgesic drugs including opioids. Better knowledge of the pathophysiological mechanisms underlying nerve injuryinduced pain is necessary to develop new and more efficacious therapies.

Peripheral nerve trauma often leads to a state of sensitization caused by complex mechanisms involving both peripheral and central events and processing. The sensitized state is characterized by an abnormal responsiveness of the somatosensory system including increased sensitivity to tactile and thermal stimuli. Experimental animal models exhibiting signs of neuropathic pain-like behavior enable the study of underlying neurochemical and neurophysiological changes. Our studies indicate that activation of the glutaminergic NMDA receptor by phosphorylation in the spinal dorsal horn is augmented in nerveinjured animals with pronounced tactile and cold hypersensitivity, suggesting that NMDA receptor phosphorylation represents one mechanism of sensitization. Furthermore, our studies indicate that there is an increase of the releaseable pool of the excitatory neuropeptide substance P at late postoperative times following nerve injury. It may be hypothesized that this change relates to an altered sensory processing or to adaptive responses associated with recovery and regeneration.

Electrical stimulation of the spinal cord (spinal cord stimulation; SCS) has developed into an indispensable tool in chronic pain management and about 60-70% of wellselected patients suffering from nerve injury-induced pain obtain satisfactory pain relief. However, despite research in recent years the mechanisms behind the beneficial effects of SCS are poorly understood. Increased knowledge of these mechanisms would facilitate further advancement and improve clinical efficacy of SCS. The present results show that SCS effectively attenuates spinal C fiber-evoked long-term potentiation produced by intense high-frequency electrical stimulation of the sciatic nerve. Furthermore, we demonstrate that anticonvulsant (gabapentin and pregabalin) and adrenoceptor active (clonidine) substances in low, by themselves ineffective, doses in combination with SCS can suppress hypersensitivity signs induced by experimental nerve injury in animals non-responsive to SCS alone. These findings provide a base for clinical trials with the concurrent use of SCS and either gabapentin/pregabalin or clonidine for the management of neuropathic pain of peripheral origin.

This thesis contributes to the understanding of the mechanisms underlying nerve injuryinduced pain, and of the mode of action of SCS and its enhancement by pharmacological adjuvants.