Estudo do papel dos canais de potássio sensíveis a ATP (KATP) na função de neurônios nociceptivos primários.

Abstract

This research analyzed the role of ATP-sensitive potassium (KATP) channels in regulating the resting potential of primary nociceptive neurons and their influence in models of pain and hyperalgesia. The main objective of the study was to analyze the impact of glibenclamide (an inhibitor of KATP channels) and diazoxide (an activator of these channels) on neuronal excitability in vitro and pain sensitivity in animals. To this end, studies were conducted in primary cultures of rat dorsal root ganglia (DRG), using confocal microscopy and the fluorescent marker DiBAC4(3) to evaluate changes in membrane potential. At the same time, behavioral experiments analyzed the mechanical hyperalgesia caused by carrageenan and the chemical nociception caused by capsaicin in rats that received the drugs intrathecally. The in vitro results indicated that glibenclamide, at the concentrations tested (1 μM, 10 μM and 100 μM), caused significant depolarization of the neuronal resting potential by blocking KATP channels, reducing K+ entry and increasing cellular activity. Diazoxide, in turn, presented a biphasic response: it initially promoted hyperpolarization, due to the activation of KATP channels, and then induced depolarization, possibly linked to compensatory mechanisms, such as the activation of voltage-sensitive calcium or sodium channels. The late depolarization occurred approximately 5 minutes after exposure to diazoxide, suggesting the involvement of secondary signaling pathways. In in vivo experiments, glibenclamide partially reduced the hyperalgesia caused by carrageenan, without significantly modifying the previous mechanical sensitivity. Diazoxide did not demonstrate an analgesic effect, indicating that the activation of KATP channels may not be sufficient to neutralize the inflammatory mediators present in carrageenan. In the nociception caused by capsaicin, both drugs intensified the pain: glibenclamide potentiated the depolarization through TRPV1, while diazoxide activated compensatory excitation pathways. These findings indicate that the modulation of KATP channels has contextual consequences, varying according to the painful stimulus and the condition of the neurons. The implications of these results are especially relevant for diabetic neuropathy, where chronic hyperglycemia reduces the activity of KATP channels, promoting neuronal hyperexcitability and persistent pain. Glibenclamide, although used in the treatment of type 2 diabetes, may aggravate neuropathic pain by blocking these channels. On the other hand, selective agonists such as diazoxide show therapeutic potential, although their efficacy needs to be improved. We conclude that KATP channels are important for maintaining the resting potential and can act as modulators of the excitability of nociceptive neurons. This mechanism explains the role of KATP channel opening in the mechanism of action of analgesic drugs. On the other hand, the data presented here suggest that glibenclamide may increase pain sensitivity. This effect should be further investigated in a future study.