Transcriptional and translational regulation of glial activation by morphine in a rodent model of neuropathic pain.
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 minipumps were implanted to deliver saline or morphine s.c. (1 or 10 mg/kg) or i.t. (5 or 20 nmol/h). Mechanical allodynia developed immediately after spinal nerve transection; this hypersensitivity was reversed with both low- and high-dose morphine by either route. Tolerance to antiallodynia developed after 3 days of i.t. morphine and after 6 days of s.c. morphine, indicating hastened tolerance following i.t. delivery. Analysis of mRNA revealed that s.c. morphine treatment did not lead to increases in glial activation markers. In contrast, i.t. morphine caused a biphasic alteration in glial fibrillary acidic protein (GFAP) and integrin alpha M mRNA. Protein levels for GFAP were elevated after s.c. and i.t. 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 i.t. morphine. Furthermore, we suggest that enhanced neuroimmune activation after i.t. dosing contributes to the hastened development of analgesic tolerance seen in these animals.
Tawfik
V L
VL
Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire, USA.
LaCroix-Fralish
M L
ML
Nutile-McMenemy
N
N
DeLeo
J A
JA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D016177:Macrophage-1 Antigen / Q000235:genetics*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019966:Substance-Related Disorders; D014158:Transcription, Genetic
D005904:Glial Fibrillary Acidic Protein; D016177:Macrophage-1 Antigen; D009020:Morphine