Studying Independent K<i>cna</i>6 Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation

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dc.contributor.authorPeck, Liam J.
dc.contributor.authorPatel, Ryan
dc.contributor.authorDiaz, Paula
dc.contributor.authorWintle, Yolanda M.
dc.contributor.authorDickenson, Anthony H.
dc.contributor.authorTodd, Andrew J.
dc.contributor.authorCalvo, Margarita
dc.contributor.authorBennett, David L. H.
dc.date.accessioned2025-01-20T22:05:18Z
dc.date.available2025-01-20T22:05:18Z
dc.date.issued2021
dc.description.abstractThe potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes of myelinated primary afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study, we compared two mouse models of constitutive Kv1.6 knock-out (KO) achieved by different methods: traditional gene trap via homologous recombination and CRISPR-mediated excision. Both Kv1.6 KO mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice (Kcna6lacZ) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism, and we found that their central primary afferent pre -synaptic terminals developed a striking neurodegenerative phenotype involving accumulation of lipid species, development of "meganeur-ites," and impaired transmission to dorsal horn wide dynamic range neurons. The anatomic defects were absent in CRISPR-mediated Kv1.6 KO mice (Kcna6-/-) but were present in a third mouse model expressing exogenous LacZ in nociceptors under the control of a Nav1.8-promoted Cre recombinase. LacZ reporter enzymes are thus intrinsically neurotoxic to sensory neurons and may induce patho-logic defects in transgenic mice, which has confounding implications for the interpretation of gene KOs using lacZ. Nonetheless, in Kcna6-/-mice not affected by LacZ, we demonstrated a significant role for Kv1.6 regulating acute noxious thermal sensitivity, and both mechanical and thermal pain-related hypersensitivity after nerve injury.
dc.fuente.origenWOS
dc.identifier.doi10.1523/JNEUROSCI.0187-21.2021
dc.identifier.eissn1529-2401
dc.identifier.issn0270-6474
dc.identifier.urihttps://doi.org/10.1523/JNEUROSCI.0187-21.2021
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94135
dc.identifier.wosidWOS:000717466100001
dc.issue.numero44
dc.language.isoen
dc.pagina.final9162
dc.pagina.inicio9141
dc.revistaJournal of neuroscience
dc.rightsacceso restringido
dc.subjectgangliosides
dc.subjectKv1
dc.subject6
dc.subjectLacZ
dc.subjectneuropathic pain
dc.subjectnociception
dc.subjectpain
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleStudying Independent K<i>cna</i>6 Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation
dc.typeartículo
dc.volumen41
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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