Activity-dependent treatments for neuropathic pain

Abstract

The onset and maintenance of neuropathic pain following a peripheral nerve injury involves many mechanisms such as changes in transduction, central or peripheral sensitization, and numerous plastic changes at the central level. Usual pharmacological treatments are not sufficient to alleviate the effects of hyperalgesia or allodynia produced by neuropathic pain. Therefore, in this thesis two activity-dependent treatments such as treadmill exercise and electrical stimulation are studied to observe the hypoalgesic effects produced and the molecular mechanisms involved in these beneficial changes. In the first two chapters of this thesis a novel protocol of treadmill exercise is shown, by increasing the velocity progressively during one hour (iTR). It has been shown that other protocols of treadmill ameliorate functional recovery after peripheral nervous system injury but, depending on intensity and duration, different effects have been described. In the first chapter, using an experimental model of neuropathic pain consisting in the section and repair of the sciatic nerve in a rat (SNTR), we found that iTR protocol reduces hyperalgesia by recoding of spontaneous neural activity, reducing neurotrophins levels to counteract nociceptive collateral sprouting, preventing the disruption of chloride cotransporters like NKCC1 and KCC2 to maintain central inhibition and counteracting microglial reactivity at central areas. iTR also positively reduced hyperalgesia in the lateral sciatic area demonstrating that the iTR hypoalgesic effect is not exclusively limited to the blockade of collateral sprouting in the periphery. Changes at central sensory circuits are also important. At the second chapter we found that iTR also increased the activity of serotonergic and noradrenergic projections from brainstem centers partially restoring the central disinhibition induced after the nerve injury. In the third chapter of this thesis, we evaluate the use of peripheral nerve stimulation (PNS) as a passive activity-dependent treatment for neuropathic pain. The therapeutic outcome together with the pattern of peripheral nerve activation, are closely related to the differences in the type and location of electrode, intensity and frequency of stimulation. For this purpose we evaluated two different experimental models as candidates. The spared nerve injury model (SNI) was the initial choice but PNS had very discrete effects in the reduction of mechanical hyperalgesia compared to SNTR. In a preliminary work, we discerned the frequency of stimulation producing the better reduction of hyperalgesia with acute stimulation after injury. Then, we improved the type of electrode and location by designing a system to make chronic stimulation available. We show some results for acute, repetitive acute and chronic stimulation protocols but the best stimulation protocol in reducing mechanical hyperalgesia was iCES protocol. Similarly to iTR, iCES consists of an increasing-frequency pattern of stimulation. We found that iCES triggers a series of changes at central levels, such as the restoration of expression of KCC2 and β2 receptor that act directly on the increase of GABA release in spinal cord facilitating together with the decrease of microglial and astrocytic reactivity, the reduction of mechanical hyperalgesia produced after SNTR.

Date of Award	30 Oct 2017
Original language	English
Supervisor	Stefano Cobianchi . (Director) & Xavier Navarro Acebes (Director)