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

Author(s)

de Andrade, Emerson Magno ^{[1, 2]} ; Martinez, Raquel C. R. ^[2] ; Pagano, Rosana L. ^[2] ; Lopes, Patricia S. S. ^[2] ; Auada, Aline V. V. ^[3] ; Gouveia, Flavia V. ^[2] ; Antunes, Geiza F. ^[2] ; Assis, Danielle V. ^[2] ; Lebrun, Ivo ^[3] ; Fonoff, Erich T. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Sch Med, Dept Neurol, Sao Paulo, SP - Brazil

^[2] Hosp Sirio Libanes, Lab Neurosci, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Butantan Inst, Biochem & Biophys Lab, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF NEUROSURGERY; v. 132, n. 1, p. 239-251, JAN 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 11/08575-7 - The role of dopaminergic modulation in the lateral nucleus of amygdala during active avoidance response
• Grantee: Raquel Chacon Ruiz Martinez
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 15/26079-8 - Participation of descending serotonergic analgesia pathway and changes in inflammatory and neurodegenerative response in the treatment of neuropathic pain by transcranial direct-current stimulation
• Grantee: Rosana de Lima Pagano
• Support Opportunities: Regular Research Grants