Nerve growth factor governs the enhanced ability of opioids to suppress inflammatory pain

Nerve growth factor (NGF) regulates sensory neuron phenotype by elevated expression of ion channels and receptors contributing to pain. Peripheral opioid antinociception is dependent on sensory neuron mu opioid receptor (MOR) expression, coupling and efficacy. This study investigates the role of NGF in the upregulation of the number and efficacy of sensory MORs rendering sites of painful inflammation more susceptible to opioids. We identified co-localization of MOR with calcitonin gene-related peptides (CGRP) and with the NGF receptors tyrosine receptor kinase (TrkA) and p75(NTR) within rat dorsal root ganglia (DRG). We showed that unilateral hind paw inflammation induced with Freund's complete adjuvant (FCA) or intraplantar (i.pl.) NGF increased NGF's retrograde transport and MOR expression in TrkA positive DRG which was prevented by the disruption of this NGF transport. MOR upregulation in DRG was followed by enhanced axonal MOR transport towards peripheral nerve terminals and subsequent increase of MOR-ir nerve fibres within skin. Furthermore, peripheral antinociception elicited by i.pl. fentanyl was naloxone reversible and potentiated exclusively in inflamed and NGF-treated paws. Both FCA- and NGF-induced effects occurring through DRG to peripheral nerve fibres and the potentiation of antinociception were abrogated by NGF neutralization. Therefore, our results suggest that NGF not only contributes to inflammatory pain but also governs the upregulation in the number and efficacy of sensory neuron MOR, resulting in enhanced opioid susceptibility towards better pain control. This suggests the potential to overcome the unresponsiveness to opioids of certain neuropathic pain states.