Neuropathic pain (NP), caused by nerve injury in the somatosensory nervous system, is among the most common forms of chronic pain. Current treatment for neuropathic pain is largely unsatisfactory, causing adverse side effects. The NGF system, as a key player in the onset and progression of pain signals in sensory neurons and of inflammation at lesion sites, has emerged as a promising target for the treatment of neuropathic pain and chronic pain. The laboratory in which I worked for my thesis had previously demonstrated that anti-NGF (mAb αD11) and anti-TrkA (mAb MNAC13) monoclonal antibodies induce an effective analgesic effect in NP murine models, that remains up to 21 days after the last dosage (Ugolini et al 2007; Covaceuszach et al 2012). To understand the role of the NGF system in NP, both as a crucial regulator and a potential therapeutic target, I evaluated in a mouse model of NP: a. the time course and the duration of the analgesic effect following the anti-NGF and anti-TrkA antibody treatment; b. the gene expression changes during and after the anti-NGF and anti-TrkA treatments in dorsal root ganglia(DRG), spinal cord (SC) and anterior cingulate cortex (ACC); c. the bioinformatic comparative study of the pain-specific and antibody-specific gene expression fingerprinting in the DRG. The behavioural and transcriptomic data indicate that anti-NGF and anti-TrkA antibodies counteract NP in the chronic constriction injury (CCI) model, showing a very long-lasting analgesic effect and induction of regenerative processes. Both anti-NGF and anti-TrkA antibodies induce analgesia, but with different dose and time-dependent effects: some differences are evident shortly after the CCI induction, while on a longer time scale they converge into a similarly effective analgesic phenotype. This suggests that they follow partially different pharmacological mechanisms. This data is supported more clearly by the transcriptomic profile: both antibodies modulate a large set of genes in the peripheral nervous system (DRG). In the central nervous system (spinal cord and cortex), the anti-NGF induces a large transcriptional modulation, while the anti-TrkA affects only a very small number of mRNAs in the same tissues. The two antibodies modulate largely different genes peripherally in DRGs, although acting on the same signalling system. Indeed, the differentially expressed genes (DEGs) modulated by the two antibodies in DRGs show only a partial overlap. Gene categories affected by the two treatments include synaptic components, immune system, inflammation, ionic channels, synaptic signalling. A minimal set of thirty mRNAs whose expression was reverted in common by the two antibodies, across all times, was identified. The DEGs regulated in common by the anti-TrkA and anti-NGF mAbs in DRGs reveal a number of potential new targets that might be linked to long lasting analgesia. Among these, the attention was focused on N6amt1. The results presented in this thesis identify a remarkably long-lasting analgesic effect of anti-NGF and anti-TrkA mAbs, that is likely due to the onset of a new analgesic transcriptional program, or to the reconstitution of a pre-lesion expression profile. This study is the first direct transcriptomic comparison of the analgesic effects of anti-NGF and anti-TrkA antibodies in a well characterized neuropathic pain model. The results strongly support the importance of NGF and TrkA for the pharmacological control of NP and the characterization of new and more specific molecular targets.
Understanding the long-lasting analgesic effect of anti-NGF and anti-TRKA antibodies in a mouse model of neuropathic pain / Cerna, Renata. - (2021 Jan 29).
|Titolo:||Understanding the long-lasting analgesic effect of anti-NGF and anti-TRKA antibodies in a mouse model of neuropathic pain|
|Data di pubblicazione:||2021-01-29|
|Settore Scientifico Disciplinare:||Settore BIO/09 - Fisiologia|
|Parole chiave (inglese):||anti-NGF - analgesic effect; anti-TrkA - analgesic effect; neuropathic pain (mouse)|
|Editore:||Scuola Normale Superiore|
|Appare nelle tipologie:||9.1 Tesi di Dottorato|