Peritumoral Administration of peripherally acting opioid agonist and high voltage calcium channel inhibitors for the management of cancer induced bone pain

Abstract

Nerve terminals within the tumor microenvironment as potential pain-mitigating targets for local infiltration analgesia (LIA) is relatively less explored. In this thesis, we undertook an indepth examination into the role of key analgesics administered as LIA (peri tumoral administration) in a model of cancer-induced bone pain (CIBP). The animal model of CIBP was utilized as a surrogate for understanding how local nerve innervation in the tumor vicinity could be utilized to mitigate tumor induced pain. CIBP was induced by administration of allogenic MRMT1 breast cancer cells in the proximal tibia of rats, and tumor mass characterized using radiogram, micro-CT, and histological analysis. In vitro responsiveness to key analgesics targeting the and#948;-opioid receptor (DOPr), voltage-gated Ca2+ channels and TRPV1 channels was assessed using ratiometric Ca2+ imaging in sensory neurons innervating the tumor site. Effectiveness of locally infiltrated analgesics administered independently or in combination was assessed by quantifying evoked limb withdrawal thresholds at the tumor site and hind paw, 2-weeks after tumor induction. No significant differences were observed in the protein and mRNA expression levels of DOPr, N-type Ca2+ channel, L-type Ca2+ channel, and TRPV1 channels in the lumbar dorsal root ganglion neurons (DRGs)harvested from CIBP animals and the control group. Baseline and peak intraneuronal calcium levels were altered in CIBP neurons compared to controls. Evoked Ca2+ transients in DRG neurons from CIBP animals were significantly reduced in response to treatment with compounds targeting the DOPr, N-, L-type Ca2+ channels and TRPV1 channels. Behaviourally, evoked hyperalgesia at the tumor site was strongly mitigated by LIA injection of the DOPr agonist and T-type calcium antagonist, via its activity on bone afferents. Results from this study suggest that nerve terminals at the tumor site could be potentially utilized as targets for specific analgesics, using local infiltration analgesia. In conclusion, this..