Received for publication January 10, 2005.
Revised February 26, 2005.
Accepted for publication February 28, 2005.

Transcriptional and Translational Regulation of Glial Activation by Morphine in a Rodent Model of Neuropathic Pain

Abstract

Glial cells function in maintenance of homeostasis as well as in pathophysiology. In this study, we determined the time course of spinal glial cell activation during the development of morphine analgesic tolerance in an L5 spinal nerve transection rodent model of neuropathic pain. We also sought to assess whether the method of morphine administration affected neuroimmune activation at the levels of transcription and translation. Rats received L5 spinal nerve transection or no surgery on day 0. On day 6 post-transection, osmotic mini-pumps were implanted to deliver saline or morphine subcutaneously (1 or 10 mg/kg) or intrathecally (5 or 20 nmol/hr). Mechanical allodynia developed immediately after spinal nerve transection; this hypersensitivity was reversed with both low and high dose morphine by either route. Tolerance to anti-allodynia developed after 3 days of intrathecal morphine and after 6 days of subcutaneous morphine, indicating hastened tolerance following intrathecal delivery. Analysis of mRNA revealed that subcutaneous morphine treatment did not lead to increases in glial activation markers. In contrast, intrathecal morphine caused a biphasic alteration in GFAP and ITGAM mRNA. Protein levels for GFAP were elevated after both subcutaneous and intrathecal administration of morphine, however induction was further enhanced in the latter group. Here we show for the first time that there is differential recruitment of transcriptional and translational mechanisms of glial activation by systemic and intrathecal morphine. Further, we suggest that enhanced neuroimmune activation after intrathecal dosing contributes to the hastened development of analgesic tolerance seen in these animals.

Key words: Astrocytes, Cytokines, Gene regulation, Microglia, Neuroimmune activation, Spinal Glia