Investigation of neuroplasticity associated with the therapeutic effects of electrical cortical stimulation in animal models of complex painful syndromes

Abstract

Neuropathic pain is considered a pathology itself because the perception of pain is disproportionately exaggerated, being evoked by innocuous stimuli or being spontaneously generated, missing the alert character of physiological pain. Besides its genesis be linked to the obvious lesions of the nervous system, neuropathic pain is the main symptom of some complex syndromes in which the nervous tissue is virtually absent of damage, for this reason being grouped under the denomination of Dysfunctional Pain. Fibromyalgia and Complex Regional Pain Syndrome-type 1 (CRPS-1) are two members of this category with considerable prevalence in population. While knowledge about neuropathic pain advanced in later years, the absence of animal models to study dysfunctional pain has hindered the proportional increase in understanding its underlying mechanisms. Similarly to neuropathic pain of diverse etiology, painful syndromes don't have specific treatment, being managed with the same classes of drugs used for other chronic pain states. Also, like neuropathic pain, a great percentage of population suffering with these syndromes is refractory for pharmacologic therapeutics. An emerging alternative in the last few years is the electrical motor cortex stimulation (MCS). This approach has obtained expressive results in the treatment of refractory neuropathic pain. Albeit the mechanisms involved in MCS-induced analgesia are still poorly understood, its effect should be linked to the modulation of synaptic plasticity in neural structures composing the nociceptive system. Trophic factors of the neurotrophin family are important elements of neuroplastic phenomena that have been extensively studied, among which stands out BDNF (brain derived neurotrophic factor). The activity of this neurotrophin, through its receptor TrkB, trigger diverse signaling cascades leading to rapid effects by ion channels modulation and long term effects by transcription factors activation, e.g. CREB. The therapeutic potential of neurotrophins leads to recent discovery of new members of this family of trophic factors, among them MANF (mesencephalic astrocyte-derived neurotrophic factor) and CDNF (cerebral dopamine neurotrophic factor) highlighted by its distribution in central nervous system and by its role in protection and restoration of injured dopaminergic neurons. Due to the key role of dopaminergic neurons in the circuitry associated to motor cortex, as well as in brain structures involved in affective aspects of pain processing, the aim of this study is to investigate the influence of MCS in the expression pattern of these neurotrophins in structures of nociceptive system, as well as its putative neuroplastic effect in animal models of Fibromyalgia and CRPS-1. To do this, the experimental model of Fibromyalgia will be induced by sub-chronic administration of reserpine and the experimental model of CRPS-1 by induction of long-term ischemia followed by reperfusion in rat hind paws. The MCS will be of transdural type. The proteins levels (BDNF, MANF, CDNF, CREB and TrkB) will be evaluated by western blott and gene expression (selected ion channels) by real-time PCR in the following structures: thalamus, periaquedutal gray, anterior cingulate cortex and spinal cord. By this way, we expect to understand the role of some neurotrophic factors and its underlying signaling cascades on the mechanisms linked to the MCS analgesic effect.