eprintid: 34805 rev_number: 20 eprint_status: archive userid: 8141 dir: disk0/00/03/48/05 datestamp: 2024-05-14 09:17:50 lastmod: 2024-05-16 13:53:13 status_changed: 2024-05-14 09:17:50 type: doctoralThesis metadata_visibility: show creators_name: Tolou Dabbaghian, Bahardokht title: Use of pharmaceutical and transgenic interventions in dissection of neuropathic pain mechanisms in spinal cord injury subjects: ddc-500 subjects: ddc-570 divisions: i-140001 adv_faculty: af-14 keywords: Neuropathic pain Pregabalin cterms_swd: Spinal cord injury cterms_swd: Hyperalgie cterms_swd: Spinal cord abstract: After experimental spinal cord injury (SCI), the emergence of neuropathic pain below the injury site is linked to heightened structural plasticity of nociceptive fibers into deeper laminae of the dorsal horn. I have examined the role of prophylactic pregabalin (PGB), a commonly prescribed drug for SCI patients following neuropathic pain development, on this aberrant plasticity and the development of neuropathic pain. Prophylactic PGB administration (46 mg/kg, i.p., 2x/day, for 7 days) effectively averted mechanical allodynia and the plasticity of peptidergic nociceptors into laminae III-IV in the lumbar spinal cord of male and female C57BL/6J mice subjected to a T11 moderate contusion. These beneficial effects against mechanical allodynia and the plasticity of nociceptive fibers persisted for up to two weeks post-PGB discontinuation. To learn more about the specific role of nociceptors and their voltage-gated calcium channel (VGCC) α2-δ2 subunit (Cacna2d2) −a selective PGB target− in the development of the neuropathic pain and aberrant plasticity I employed SNSCacna2d2 mice with a partial knockout of the α2-δ2 subunit specifically in nociceptors. Remarkably, these mice did not manifest thermal hyperalgesia nor mechanical allodynia postSCI, as confirmed by Hargreaves, von Frey hair filaments, and the place escape/avoidance paradigm. Importantly, non-noxious mechanical hindpaw stimulation induced dorsal horn activation (c-fos) with significantly lower activation in both the PGB-treated and partial knockout mice. Laminae III-V of the dorsal horn exhibited the highest neuronal activation, aligning with the observed plasticity. Utilizing 3D imaging of nociceptor-labeled transgenic mice (SNStdTomato), this study reveals a post-SCI increase in volume of nociceptors in lower laminae of the dorsal horn, specifically starting from lamina III. This expansion suggests ventral sprouting rather than lateral. This thesis work underscores the pivotal role of nociceptors in neuropathic pain development following SCI, indicating their plasticity into deeper laminae establishes new connections transmitting mechanical allodynia potentially through wide dynamic neurons. date: 2024 id_scheme: DOI id_number: 10.11588/heidok.00034805 own_urn: urn:nbn:de:bsz:16-heidok-348052 date_accepted: 2024-05-07 advisor: HASH(0x5644f2e99198) language: eng bibsort: TOLOUDABBAUSEOFPHARM full_text_status: restricted place_of_pub: Heidelberg citation: Tolou Dabbaghian, Bahardokht (2024) Use of pharmaceutical and transgenic interventions in dissection of neuropathic pain mechanisms in spinal cord injury. [Dissertation] document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/34805/1/Thesis-Bahar%20Tolou.pdf