Title

 

Authors

G. Vincelli¹, A. Bedini¹ and S. Spampinato^1
 
1Dept. of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy

 

Abstract

Chronic pain is widespread in the western world: one of the most common conditions is neuropathic pain, which can be conceptualized as the result of a process of aberrant learning, associated with phenomena of maladaptive plasticity in the nervous system, where chronic inflammation and glial activation develop in parallel. Glial cells are activated at multiple sites along the pain pathway following peripheral trauma or inflammation, thus inducing production and release of several pro-inflammatory cytokines which act in a autocrine/paracrine fashion, drive pain amplification and contribute to maintain neuropathic pain. A new scenario in pain pharmacology is unveiled, leading to new and interesting research prospects: until recently, the development of analgesics was directed solely towards neuronal targets, and only recently studies started to concern of cellular and molecular interaction between neuronal cells, inflammatory cells and molecules, and the glia involved in the genesis and mantainance of neuropathic pain.  At this regard, it is relevant how endogenous opioid ligands (such as endomorphins) have a notable antinociceptive effect in animal models of neuropathic pain whereas morphine is ineffective or even noxious (Jensen et al., 2009). This could be partly explained by the fact that glial cells may express μ opioid receptor (MOR) which have high affinity for morphine and may directly activate glial cells, causing the release of pro-inflammatory molecules (Watkins et al., 2005). Interestingly, up to now, MOR expression in glial cells has been poorly studied. Recently, it has been reported that morphine can bind directly to the Toll-Like Receptors (TLRs), which are expressed in the glia, thus activating these cells and contributing to neuropathic pain mantainance (Hutchinson et al., 2007).
Furthermore the nociceptin/nociceptin receptor (N/OFQ-NOP) system is activated by inflammatory stimuli at spinal level: this supports the hypothesis that the nociceptin/NOP receptor system may contribute to the complex neuron-glia cross-talk in the modulation of neuropathic pain.
The aim of this study has been to investigate the expression and intracellular signalling of MOR and NOP in a model of human glial cells (U-87 MG) exposed to proinflammatory stimuli. We found that TNFα incrases the expression of MOR and decreases the expression of NOP in U-87 MG cells: MOR up-regulation and NOP downregulation by TNFα were both concentration- and time-dependent, with the maximal effect after 48 h of exposure and at the concentration of 10 ng/ml for MOR and 5 ng/ml for NOP. LPS-mediated effects on MOR and NOP mRNA levels have been also explored, resulting MOR transcription significantly upregulated.
The involvment of signal transduction pathways triggered by inflammatory stimuli has been investigted by employing a specific NF-kB reporter plasmid and any effect elicited by MOR and NOP ligands has been also investigated, aiming to confirm that these compounds may represent novel therapeuthic strategies to counteract the neurodegenerative effects determined by actvated glial cells.
 
Jensen TS et al. (2009) Curr Opin Neurol. 22,467-74.
Watkins LR et al. (2005) Trends Neurosci. 28,661-9.
Hutchinson MR et al. (2007) ScientificWorldJournal. 7,98-111.