Spinal cord stimulation in neuropathy : experimental studies of biochemistry and behaviour

Abstract

Neuropathic pain, presenting with cutaneous hypersensitivity, i.e. allodynia, dysesthesia and hyperalgesia, is often difficult to manage with pharmacotherapy, but may be effectively alleviated by electric spinal cord stimulation (SCS). However, the mode of action of SCS is still poorly understood. The principal aims of the present studies were: 1) to investigate mechanisms involved in the development of neuropathy following sciatic nerve injury; 2) to explore biochemical mechanisms underlying the effect of SCS in neuropathy; and 3) to examine whether it is possible to potentiate or enhance the effects of SCS by concomitant administration of receptor active substances.

It is believed that cutaneous hypersensitivity after nerve injury in rats mimics allodynia associated with neuropathic pain in patients. In rats, the incidence of "allodynia" is highly variable, but it can be influenced by pre-emptive alteration of spinal excitability: enhanced by intrathecal administration of GABAB antagonists or C-fiber stimulation and reduced by a GABAB agonist. A novel method of creating a lesion of the sciatic nerve by a local photochemical reaction has provided an exceptionally high incidence of tactile allodynia. The presence of allodynia after nerve lesions appears to be inversely related to the degree of up-regulation of galanin immunoreactivity in the DRG and the DH. This finding supports the idea that galanin may have a protective function in the development of neuropathic pain. It was further found that the presence of tactile allodynia is associated with augmented levels of extracellular glutamate (GLU) and aspartate (ASP) while GABA is decreased, as shown by microdialysis from the spinal DH in nerve lesioned rats. SCS produced a delayed increase in GABA release, but an immediate decrease in the GLU and ASP levels. These effects were only observed in rats responding to SCS with suppression of tactile allodynia. The effects of SCS were counteracted by the application of a GABAB antagonist via the microdialysis probe. Behavioural experiments revealed that rats with tactile allodynia, which did not respond to SCS, can be transformed into SCS responders by concomitant administration of low, and by itself ineffective doses, of baclofen. Similar enhancing effects on SCS have been observed with i.t. administration of an adenosine A I receptor agonist, (R-PIA). Baclofen and R-PIA in even lower doses can synergistically potentiate the SCS effect in non-responding rats.

It has been questioned whether SCS may also alleviate pain classified as nociceptive. Therefore, we have studied the effect of SCS on a model of nociceptive (inflammatory) pain induced by local injection of carrageenan in the plantar hind paw. This leads to swelling of the paw and marked hyperalgesia lasting up to 9 days. Initially SCS aggravated the hyperalgesia, whereas between day 3 and 5 it instead attenuated the hyperalgesia. This effect may be mediated by an A-fiber dependent mechanism.

Conclusion: Variations in spinal neuronal excitability influence the development of allodynia due to nerve lesion. Such nerve injury results in deficient GABA function and enhanced release of EAA in the DH associated with the development and maintenance of neuropathy. SCS can alleviate allodynia via a GABAergic mechanism thereby controlling EAA release. SCS effects on allodynia can be enhanced by concomitant administration of GABAB and/or adenosine A1 receptor agonists in non-responding rats. These findings provide a rationale for further trials to enhance the clinical pain-relieving effect of SCS.