Papel de los receptores sigma-1 en la transmisión y modulación nociceptiva a través de la médula espinal

Abstract

The spinal cord is the first relay center for somatosensory inputs from peripheral receptors. Thus, modulation of spinal circuits has become an important strategy to design analgesic and anesthetic drugs. Drugs currently used in the clinic, are still not effective in many chronic pain processes. Therefore, the finding of new therapeutic targets remains essential. σ1 receptors have been studied in an attempt to elucidate their possible neuropharmacological applications in analgesia. The aim of this Thesis was to study the effects of S1RA, a selective σ1 receptor antagonist, on nociceptive transmission in mice spinal cord. To this purpose, electrophysiological recordings were performed in two different spinal cord “in vitro” models. In the first chapter of this Thesis, spinal motor responses to dorsal root stimulation (spinal reflexes) were recorded, from mice pups (6 to 10 days). Dorsal root primary afferents were activated using electrical stimulation and the motor signal generated through ventral root was registered using suction electrodes. This model was used to evaluate (1) the effects of S1RA compared to other well-stabilized analgesics in cords from näive animals, (2) the effects of S1RA in cords from animals pretreated with carrageenan (inflammation model) and (3) the interaction between S1RA and morphine. For the second chapter, a longitudinal slice of adult spinal cord was developed. Single units from superficial laminae were registered. Multielectrode arrays were used for recording electrical activity evoked by dorsal root stimulation and spontaneous intrinsic activity. This model was used to (1) characterize neuronal behavior in cords from näive mice and cords from neuropathic mice (SNI), (2) to evaluate the pharmacological effects of NMDA, AMPA and substance P blockers, on spontaneous and induced neuronal responses and (3) to evaluate the effect of S1RA in superficial neurons in cords from näive animals and animals that had received an inflammatory (carrageenan) or a neuropathic (SNI) treatment. Results indicate that, S1RA has an inhibitory action similar to that of other commercial analgesics. These depressant effects of S1RA in cords from inflamed mice are slightly greater than the effects shown in cords from näive mice. No significant interaction between S1RA and morphine has been found. Recordings from superficial laminae neurons have not shown susbstantial differences in evoked or spontaneous electrical activity between cords from näive and neuropathic mice. Pharmacological experiments show that only blockade of AMPA receptors produces inhibitory effects in responses to single electrical stimuli. Blockade of AMPA-, NMDA- and substance P receptors produces inhibitory effects in responses to repetitive electrical stimuli and spontaneous activity. S1RA showed no effect, on either spontaneous or induced activity, in neurons from superficial laminae from näive animals. However, S1RA, showed an inhibitory effect on spontaneous activity in animals pretreated with carragennan. The compound also had inhibitory effects on spontaneous activity and on responses to repetitive stimuli in neuropathic animals. The S1RA drug has been shown to have effects at the spinal level, and these effects were shown to be higher in a carrageenan and neuropathy model. These results seem to confirm the involvement of σ1 system in pathological pain and its potential as a therapeutic target for this type of process.