Nerve Growth Factor/Tyrosine Kinase A Receptor Pathway Enhances Analgesia in an Experimental Mouse Model of Bone Cancer Pain by Increasing Membrane Levels of δ-Opioid Receptors

Abstract

Background The role of Nerve growth factor (NGF)/tyrosine kinase A receptor (TrKA) signaling, which is activated in a variety of pain states, in regulating membrane-associated δ-opioid receptor (mDOR) expression is poorly understood. We hypothesized that elevated NGF in bone cancer tumors could upregulate mDOR expression in spinal cord neurons, and that mDOR agonism might alleviate bone cancer pain (BCP). Methods BCP was induced by inoculating Lewis lung carcinoma cells (LLC) into the femoral marrow cavity of adult C57BL/6J mice of both sexes. Nociceptive behaviors were evaluated by von Frey and Hargreaves tests. Protein expression in the spinal dorsal horn of animals was measured by biochemical analyses and excitatory synaptic transmission was recorded in miniature excitatory synaptic currents (mEPSCs). Results We found that mDOR expression was increased in BCP mice (BCP vs. sham, mean ± SD: 0.18 ± 0.01 g vs. mean ± SD: 0.13 ± 0.01 g, n = 4, P < 0.001) and that administration of DOR agonist, deltorphin 2 (Del2), increased nociceptive thresholds [Del2 vs. vehicle, median (25th, 75th percentiles): 1.00 (0.60, 1.40) g vs. median (25th, 75th percentiles): 0.40 (0.16,0.45) g, n = 10, P = 0.001] and reduced mEPSC frequency in lamina Ⅱ outer neurons (Del2 vs. baseline, mean ± SD: 2.21 ± 0.81 Hz vs. mean ± SD: 2.43 ± 0.90 Hz, n = 12, P < 0.001). Additionally, NGF expression was increased in BCP mice (BCP vs. sham, mean ± SD: 0.36 ± 0.03 vs. mean ± SD: 0.16 ± 0.02, n = 4, P < 0.001), and elevated NGF was associated with enhanced mDOR expression via TrKA signaling. Conclusion Activation of mDOR produce analgesia that is dependent on the upregulation of the NGF/TrKA pathway by increasing mDOR levels under conditons of BCP in mice.