The Molecular and Behavioural Effects of Glial Modulators Propentofylline and PJ34 in a Rodent Model of Neuropathic Pain
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Neuronal-glial interactions play an important role in the development of neuropathic (NP) pain states. Earlier studies in our laboratory suggest a role for activated glia in morphine-induced delta opioid receptor (DOR) trafficking by altering DOR functional competence. Thus, chronic treatment with the glial inhibitor, propentofylline (PF) blocks the anti-allodynic and anti-hyperalgesic effects of the DOR agonist deltorphin II. The present study aimed to determine whether NP pain-induced changes in DOR function and trafficking are dependent on glial activation. The first global aim of this study was to determine the molecular and behavioural effects of glial activation by two glial inhibitors, PF and PJ34 in a model of neuropathic pain. Glial activation was assessed via changes in specific proteins using fluorescent immunohistochemistry (IHC). Neuropathy-induced c-Fos activation was assessed by IHC and pain hypersensitivity was assessed, including mechanical allodynia and spontaneous pain. The second global aim determined the role of activated glia in changes in neuropathy-induced increases in DOR function and DOR subcellular localization using immunogold IHC and transmission electron microscopy (EM). Chronic PJ34 attenuated chronic constriction injury (CCI)-induced mircoglial, but not astrocyte activation. Chronic administration of either PF or PJ34 attenuated the CCI-induced increase in c-Fos immunoreactive expression. However, neither drug attenuated CCI-induced mechanical allodynia or spontaneous pain. Both chronic PF and PJ34 administration in NP animals attenuated the anti-allodynic effects of the DOR-selective agonist deltorphin II, suggesting glial inhibition blocks DOR function. However, chronic PF, but not PJ34, blocked the anti-allodynic effects of another DOR agonist, SNC80. These data suggest that SNC80 might be targeting a different DOR molecular species that is not affected by factors released from microglia. Finally, EM experiments revealed that chronic PF treatment prevented the CCI-induced increase in DOR trafficking providing a positive correlation between behaviour and receptor localization. This study suggests that activated glia contribute to changes in DOR function and trafficking in NP pain states. It also suggests that there is a dissociation between glial inhibition and pain hypersensitivity.