Alleviation of Trigeminal Nociception Using p75 Neurotrophin Receptor Targeted Lentiviral Interference Therapy

Abstract

Acute and chronic trigeminal (TG) neuropathies are the cause of considerable distress, with limited treatments available at present. Nociceptive neurons enriched with the vanilloid type 1 receptor (VR1) partake in pain sensation and sensitization in the TG system. While VR1 blockers with anti-nociceptive potential are of substantial medical interest, their use remains limited due to poor selectivity and lack of cell-targeting capabilities. This study describes a methodology for the alleviation of nociception via targeted depletion of VR1 in TG sensory neurons in rats. In cultured TG ganglion neurons, VR1 expression was virtually abolished by lentiviral short hairpin RNA (LV-VR1). By decorating GFP encoding LV (LV-GFP) and LV-VR1 with IgG192 for targeting TG sensory neurons enriched with the p75 neurotrophin receptor (p75NTR), transduction of a reporter GFP and VR1 depletion was achieved after injection of targeted vectors into the whisker pad. In IgG192/LV-VR1-injected rats, the behavioral response to capsaicin exposure as well as Erk 1/2 phosphorylation and VR1 current activation by capsaicin were significantly reduced. This pioneering investigation, thus, provides a proof of principle for a means of attenuating TG nociception, revealing therapeutic potential.

Selected Ionotropic Receptors and Voltage-Gated Ion Channels: More Functional Competence for Human Induced Pluripotent Stem Cell (iPSC)-Derived Nociceptors

“…RUNX1 was expressed in all TUJ1 positive iDNs ( Figure 2 B). In order to further dissect the phenotype of iDNs, the low affinity nerve growth factor receptor p75 as a broadly accepted nociceptive marker was included in the characterization [ 39 , 40 , 41 ] and p75 was shown to be required for the sensory neuron diversity by potentiating RET signaling [ 42 ], as well as RET was shown to be activated subsequently after RUNX1 expression in previously established iDN differentiation protocols [ 4 ]. We detected a robust expression of p75 in iDNs ( Figure 2 C), and ~79% of iDNs showed p75 abundance as compared with mouse DRGs (~64%) ( Figure 2 D), and therefore in conjunction with the high expression of RUNX1 resembling a non-peptidergic iDN phenotype ( Figure 2 C,D).…”

Role of Neurotrophins in Orofacial Pain Modulation: A Review of the Latest Discoveries

“…Finally, an alleviation of trigeminal nociception using p75NTR-targeted lentiviral interference therapy was performed to achieve targeted depletion of TRPV1 in TG sensory neurons in rats with positive and interesting results [92]. This research was previously described in the TG paragraph, underling that the Sp5 of the brainstem was also investigated revealing much higher expression of TrkA in Sp5 as compared to p75NTR with the opposite trend in TG [92].…”

“…Nevertheless, the BDNF topic was preferred with respect to NGF, even if by a little. One considered both BDNF and NT-3 in nociceptive pain [89], and others investigated neurotrophins' receptors [77,92,98]. Finally, in the brainstem, the trend was different.…”

“…Interestingly, p75NTR targeted lentiviral interference therapy was proposed to alleviate trigeminal nociception to achieve targeted depletion of TRPV1 in rat TG sensory neurons with novel and positive results monitoring TG and Sp5C [92]. This study introduced a therapeutic targeting strategy that provided a means to post-transcriptionally downregulate TRPV1 in TG nociceptors of adult rats in vivo [92].…”

“…O'Leary et al, 2018 [92] p75NTR targeted lentiviral interference therapy is proposed to alleviate trigeminal nociception to achieve targeted depletion of TRPV1 in rat TG sensory neurons with novel and positive results monitoring TG and Sp5C.…”