Hypertonic saline opens the perineurial barrier via metalloproteinase activation and claudin-1 regulation, thereby allowing access of hydrophilic drugs to peripheral opioid receptors. This principle may be used to specifically target hydrophilic drugs to peripheral neurons.
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 -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,
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