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

Abstract

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,

Effects of surgery and/or remifentanil administration on the expression of pERK1/2, c-Fos and dynorphin in the dorsal root ganglia in mice

“…ERK activation was observed in the perycaria of small primary afferent neurons (Donnerer et al 2005;Noguchi et al 2004;Obata et al 2003, although it also occurred in the peripheral processes of these cells (Aley et al 2001;Averill et al 2001;Dai et al 2002). Interestingly, pERK levels were found to be increased in primary afferents following exposure to nerve growth factor (NGF) (Amaya et al 2009;Averill et al 2001;Yamdeu et al 2011). ERK activation has also been shown to be responsible for the up-regulation of the brain-derived neurotrophic factor (BDNF) in the cell bodies of DRG neurons in models of peripheral inflammation and neuropathic pain (Obata et al 2003.…”

Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy

“…Mechanical pain thresholds were assessed by a paw pressure algesiometer before (baseline) and after intraplantar injections of the opioid agonist fentanyl (0.5–1.25 μg/100 μL) as previously described (11,17). Paw pressure thresholds (PPT) were expressed as raw data in grams or as percent maximum possible effect according to the following equation: (PPT postinjection – PPT basal ) / (140 cut-off – PPT basal ) to correct for differences in baseline and to set the data in relation to the maximal effect of control animals.…”

Inhibition of c-Jun NH2-terminal kinase stimulates mu opioid receptor expression via p38 MAPK-mediated nuclear NF-κB activation in neuronal and non-neuronal cells

“…In a recent in vivo study, nerve growth factor was shown to increase the number of phosphorylated p38 MAPK immunoreactive neurons expressing MOR in dorsal root ganglia, increase peripherally directed axonal transport of MOR, and increase significant potentiation, as well as enhance efficacy in fentanyl- and buprenorphine-induced dose-dependent antinociception [48]. The expression of MOR gene in P19 cells by protein synthesis inhibitors is mediated through the activation of the PI-3K and p38 MAPK pathways, and inhibiting p38 MAPK decreases the constitutively expressed MOR expression levels in NMB neuroblastoma cells [20].…”