T-type channels control the opioidergic descending analgesia at the low threshold-spiking GABAergic neurons in the periaqueductal gray

Abstract

Endogenous opioids generate analgesic signals in the periaqueductal gray (PAG). However, because cell types in the PAG are difficult to identify, its neuronal mechanism has remained poorly understood. To address this issue, we characterized PAG neurons by their electrical properties using differentially labeled GABAergic and output neurons in the PAG. We found that GABAergic neurons were mostly fast-spiking cells and could be further divided into two distinct classes: with or without low-threshold spikes (LTS) driven by T-type channels. In contrast, the PAG output neurons lacked LTS and showed heterogeneous firing patterns. To reveal the function of the LTS, we examined the mutant mice lacking the α1G T-type channels (α1G). The mutant mice lacked LTS in the fast-spiking GABAergic neurons of the PAG and unexpectedly showed impaired opioid-dependent analgesia; a similar phenotype was reproduced in PAG-specific α1G-knockdown mice. Electrophysiological analyses revealed functional expression of μ-opioid receptors in the low threshold-spiking GABAergic neurons. These neurons in the mutant lacking LTS showed markedly enhanced discharge activities, which led to an augmented inhibition of output neurons. Furthermore, the impaired analgesia observed in α1G −/− mice was reversed by blocking local GABA A receptors. These results indicate that α1G T-type channels are critical for the opioidergic descending analgesia system in the PAG.opioid-descending analgesia | α1G | morphine | stress | calcium-activated potassium channel | afterhyperpolarization

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“…117,118 The analgesic effects are mediated by serotonergic fibers arising from the PAG. Serotonergic neurotransmission in the PAG is inhibited by local GABAergic neurons.…”

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“…Thalamic relay cells fire in two distinct modes, burst or tonic, which are dictated by the state of low-threshold, voltage-gated, T-type Ca 2+ channels (39,40). Using Ca v 3.1 −/− mice, we previously demonstrated that the deletion of Ca v 3.1 T-type currents results in the absence of LTS and an increase in tonic firing in periaqueductal GABAergic neurons (30), whereas enhanced expression of T-type currents decreases tonic firing activity in thalamic relay neurons (41). In the present study, using null-mutant and MS-specific knockdown of Ca v 3.1, we demonstrated that Ca v 3.1 T-type Ca 2+ channels are involved in the Representative LFP waveforms and (E and F) corresponding averaged power spectra recorded during urethane anesthesia's theta-on state and wheel-running, respectively, in mice during the period of no application of light (black trace) and photo-inhibition period (blue trace) (n = 6).…”

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“…The LJP was corrected offline. vlPAG neurons were first identified either as projecting neurons or as interneurons, on the basis of their intrinsic membrane properties, and further classified as FS or TS according to the criteria described elsewhere (Park et al, 2010) (details in the Supplementary Material). .…”