Transcranial Direct Current Stimulation Reduces Anxiety, Depression and Plasmatic Corticosterone in a Rat Model of Atypical Generalized Epilepsy.

Affective disorders (i.e. anxiety and depression) are commonly observed in patients with epilepsy and induce seizure aggravation. Animal models of epilepsy that exhibit affective disorder features are essential in developing new neuromodulatory treatments. GEAS-W rats (Generalized Epilepsy with Absence Seizures, Wistar background) are an inbred model of generalized epilepsy showing spontaneous spike-wave discharges concomitant with immobility. Transcranial Direct Current Stimulation (tDCS) is a safe non-invasive neuromodulatory therapy used to modulate dysfunctional circuitries frequently and successfully applied in affective disorders for symptom alleviation. Here we investigated anxiolytic and antidepressant effects of tDCS in GEAS-W rats and the role of corticosterone as a possible mechanism of action. GEAS-W and Wistar rats were randomly divided into control, sham-tDCS and active-tDCS groups. Both tDCS groups received 15 sessions of sham or active-tDCS (1 mA, cathode). Behavioural tests included the Open Field and Forced Swimming tests followed by corticosterone analysis. We observed a main effect of treatment and a significant treatment by strain interaction on anxiety-like and depressive-like behaviours, with active-tDCS GEAS-W rats entering the center of the open field more often and showing less immobility in the forced swimming test. Furthermore, there was a main effect of treatment on corticosterone with active-tDCS animals showing marked reduction in plasmatic levels. This study described preclinical evidence to support tDCS treatment of affective disorders in epilepsy and highlights corticosterone as a possible mechanism of action.

Neurochemical effects of motor cortex stimulation in the periaqueductal gray during neuropathic pain

OBJECTIVE Motor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of g-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings. METHODS Male Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS. RESULTS MCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia. CONCLUSIONS These results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes

Neurochemical effects of motor cortex stimulation in the periaqueductal gray during neuropathic pain

OBJECTIVE Motor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of g-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings. METHODS Male Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS. RESULTS MCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia. CONCLUSIONS These results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes

Neurochemical effects of motor cortex stimulation in the periaqueductal gray during neuropathic pain.

OBJECTIVE: Motor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings. METHODS: Male Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS. RESULTS: MCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia. CONCLUSIONS: These results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.

The critical role of amygdala subnuclei in nociceptive and depressive-like behaviors in peripheral neuropathy.

The amygdala is an important component of the limbic system that participates in the control of the pain response and modulates the affective-motivational aspect of pain. Neuropathic pain is a serious public health problem and has a strong affective-motivational component that makes it difficult to treat. The central (CeA), basolateral (BLA) and lateral (LA) nuclei of the amygdala are involved in the processing and regulation of chronic pain. However, the roles of these nuclei in the maintenance of neuropathic pain, anxiety and depression remain unclear. Thus, the main objective of this study was to investigate the role of amygdala subnuclei in the modulation of neuropathic pain, including the affective-motivational axis, in an experimental model of peripheral neuropathy. The specific goals were as follows: (1) To evaluate the nociceptive responses and the patterns of activation of the CeA, BLA and LA in neuropathic rats; and (2) To evaluate the effect of inactivating the amygdala nuclei on the nociceptive response, anxiety and depressive behaviors, motor activity, and plasma stress hormones in animals with neuropathic pain. Thus, mechanical hyperalgesia and allodynia, and the pattern of c-Fos staining in the amygdala subnuclei were evaluated in rats with chronic constriction of the sciatic nerve, as well as sham-operated and naïve rats. Once the amygdala subnuclei involved in neuropathic pain response were defined, those subnuclei were pharmacological inactivated. The effect of muscimol inactivation on the nociceptive response (hyperalgesia and allodynia), anxiety (elevated plus-maze), depressive-like behavior (forced swim test), motor activity (open field), and plasma stress hormone levels (corticosterone and adrenocorticotropic hormone) were evaluated in sham-operated and neuropathic animals. The results showed that the anterior and posterior portions of the BLA and the central portion of the CeA are involved in controlling neuropathic pain. The inactivation of these nuclei reversed hyperalgesia, allodynia and depressive-like behavior in animals with peripheral neuropathy. Taken together, our findings improve our understanding of the neurocircuitry involved in persistent pain and the roles of specific amygdala subnuclei in the modulation of neuropathic pain, including the neurocircuitry that processes the affective-motivational component of pain.