T-type channels control the opioidergic descending analgesia at the low threshold-spiking GABAergic neurons in the periaqueductal gray.
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 alpha1G T-type channels (alpha1G(-/-)). 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 alpha1G-knockdown mice. Electrophysiological analyses revealed functional expression of mu-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 alpha1G(-/-) mice was reversed by blocking local GABA(A) receptors. These results indicate that alpha1G T-type channels are critical for the opioidergic descending analgesia system in the PAG.
Park
Cheongdahm
C
Center for Neural Science, Future Fusion Technology Laboratory, Korea Institute of Science and Technology, Seoul 136-791, Korea.
Kim
Jong-Hyun
JH
Yoon
Bo-Eun
BE
Choi
Eui-Ju
EJ
Lee
C Justin
CJ
Shin
Hee-Sup
HS
D000701:Analgesics, Opioid / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000502:physiology*; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D010487:Periaqueductal Gray / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D011963:Receptors, GABA-A / Q000378:metabolism
D000701:Analgesics, Opioid; C498197:Cacna1g protein, mouse; D020747:Calcium Channels, T-Type; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D049452:Green Fluorescent Proteins; D001640:Bicuculline