Minocycline prevents morphine-induced apoptosis in rat cerebral cortex and lumbar spinal cord: a possible mechanism for attenuating morphine tolerance.
Tolerance to the chronic administration of opioids such as morphine reduces the utility of these drugs in pain management. Despite significant investigation, the precise cellular mechanisms underlying opioid tolerance and dependence remain elusive. It has been indicated that tolerance to the analgesic effect of morphine is associated with apoptosis in the central nervous system. The aim of this study was to examine the effects of the intracerebroventricular (icv) administration of minocycline (a second-generation tetracycline) on morphine-induced apoptosis in the cerebral cortex and lumbar spinal cord of rats after morphine-induced tolerance. Different groups of rats received either morphine (ip) and distilled water (icv) or morphine and different doses of minocycline (icv) or minocycline alone once per day. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method was used to analyze apoptosis. The anti-apoptotic factors, Bcl-2 and HSP 70 and the pro-apoptotic element caspase-3 were evaluated by immunoblotting. The results indicated that minocycline attenuated the number of apoptotic cells in both the cerebral cortex and lumbar spinal cord. Immunoblotting findings showed that the amounts of anti-apoptotic agents (Bcl-2 and HSP 70) were greater in the treatment groups than in the controls in both regions. Although minocycline did not change the level of caspase-3 at the doses used with morphine but the minocycline treated rats showed a significantly lower increase in caspase-3 activity than did in the control. In conclusion, minocycline decreased the number of TUNEL-positive cells and increased the amount of anti-apoptotic factors (Bcl-2 and HSP 70), but did not change the caspase-3 content.
Hassanzadeh
Kambiz
K
Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, 66177-13446 Sanandaj, Iran. kambizhassanzadeh@gmail.com
Habibi-asl
Bohlool
B
Farajnia
Safar
S
Roshangar
Leila
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004361:Drug Tolerance / Q000502:physiology*; D008159:Lumbar Vertebrae; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D009020:Morphine; D008911:Minocycline