Nerve injury increases brain‐derived neurotrophic factor levels to suppress BK channel activity in primary sensory neurons

Abstract

Abnormal hyperexcitability of primary sensory neurons contributes to neuropathic pain development after nerve injury. Nerve injury profoundly reduces the expression of big conductance Ca2+-activated K+ (BK) channels in the dorsal root ganglion (DRG). However, little is known about how nerve injury affects BK channel activity in DRG neurons. In this study, we determined the changes in BK channel activity in different sizes of DRG neurons in a rat model of neuropathic pain and the contribution of brain-derived neurotrophic factor (BDNF) to reduced BK channel activity. The BK channel activity was present predominantly in small and medium DRG neurons, and ligation of L5 and L6 spinal nerves profoundly decreased the BK current density in these neurons. Blocking BK channels significantly increased the excitability of DRG neurons in sham control, but not in nerve-injured, rats. The BDNF concentration in the DRG was significantly greater in nerve-injured rats than in control rats. BDNF treatment largely reduced BK currents in DRG neurons in control rats, which was blocked by either anti-BDNF antibody or K252a, a Trk receptor inhibitor. Furthermore, either anti-BDNF antibody or K252a reversed reduction in BK currents in injured DRG neurons. BDNF treatment reduced the mRNA levels of BKα1 subunit in DRG neurons, and anti-BDNF antibody attenuated the reduction in the BKα1 mRNA level in injured DRG neurons. These findings suggest that nerve injury primarily diminishes the BK channel activity in small and medium DRG neurons. Increased BDNF levels contribute to reduced BK channel activity in DRG neurons in neuropathic pain.

Protease-activated receptor-2 inhibits BK channel activity in bronchopulmonary sensory neurons

“…Results from our current-clamp study show that inhibiting BK channel with paxilline significantly broadens action potential and leads to increased repetitive firing in bronchopulmonary sensory neurons, which is in agreement with the demonstrated effect of BK blockade on the excitability of dorsal root ganglion neurons [4,27]. Our results further show that pretreatment with PAR 2 -AP also significantly increases APD 50 and the number of evoked action potentials without significantly altering the resting membrane potential, a similar effect as displayed by paxilline.…”

Positive Feedback Loop of Autocrine BDNF from Microglia Causes Prolonged Microglia Activation

“…Researchers subsequently began to focus on the effect of BDNF on neuropathic pain. Substantial evidence suggests that BDNF plays a key role in synaptic transmission by potentiating the NMDA receptors present in primary afferents [18], regulating the pattern of expression and the level of activity of the transducer channels TRPA1 and TRPV1 [19], and reducing Ca 2+ -activated K + channel activity in the dorsal root ganglion (DRG) [20]. In our previous study, we demonstrated that BDNF could directly activate astrocytes in the spinal dorsal horn in a rat model of neuropathic pain [14].…”

Etiology and Pharmacology of Neuropathic Pain

“…Changes in K + Channels. Attenuation of various types of K + channel conductance also contributes to the increased excitability of DRG neurons that follows injury or exposure to inflammatory cytokines such as IL-1b (Abdulla and Smith, 2001a,b;Kim et al, 2002;Tan et al, 2006;Stemkowski et al, 2015;Cao et al, 2012;Stemkowski and Smith, 2012a;Tsantoulas et al, 2012;Waxman and Zamponi, 2014;Gonzalez et al, 2017).…”