p38 Mitogen-activated Protein Kinase Activation by Nerve Growth Factor in Primary Sensory Neurons Upregulates mu-Opioid Receptors to Enhance Opioid Responsiveness Toward Better Pain Control

Background: Sensory neuron opioid receptors are targets for spinal, epidural, and peripheral opioid application. Although local nerve growth factor (NGF) has been identified as a mediator of sensory neuron mu-opioid receptor (MOR) up-regulation, the signaling pathways involved have not been yet identified. Methods: Wistar rats were treated with intraplantar vehicle, Freund's complete adjuvant, NGF, NGF plus intrathecal p38 mitogen-activated protein kinase (MAPK) inhibitors, or NGF plus extracellular signal-regulated kinase-1/2 MAPK inhibitors. After 4 days of treatment, paw pressure thresholds of an intraplantar full (fentanyl) or partial (buprenorphine) opioid agonist were determined by algesiometry. Tissue samples from rat dorsal root ganglia were subjected to radiolabeled ligand binding, Western blot analysis, and confocal immunofluorescence. Results: Exogenous and endogenous NGF resulting from Freund's complete adjuvant inflammation produced significant potentiation and enhanced efficacy in fentanyl- and buprenorphine-induced dose-dependent antinociception, respectively. Furthermore, in the ipsilateral dorsal root ganglia, NGF produced a significant increase in MOR binding sites, proteins, and immunoreactive neurons. In parallel, phosphorylated p38-MAPK protein, the number of phosphorylated p38-MAPK immunoreactive neurons expressing MOR in dorsal root ganglia, and the peripherally directed axonal transport of MOR significantly increased. Finally, NGF-induced effects occurring in dorsal root ganglia, on axonal transport, and on the potentiation or enhanced efficacy of opioid antinociception were abrogated by inhibition of p38, but not extracellular signal-regulated kinase-1/2, MAPK. Conclusions: Local NGF through activation of the p38-MAPK pathway leads to adaptive changes in sensory neuron MOR toward enhanced susceptibility to local opioids. This effect may act as a counter-regulatory response to p38-MAPK-induced pain (e. g., inflammatory pain) to facilitate opioid-mediated antinociception.