Modulation of morphine-induced antinociception in acute and chronic opioid treatment by ibudilast.
BACKGROUND
Opioid analgesics are effective in relieving chronic pain, but they have serious adverse effects, including development of tolerance and dependence. Ibudilast, an inhibitor of glial activation and cyclic nucleotide phosphodiesterases, has shown potential in the treatment of neuropathic pain and opioid withdrawal. Because glial cell activation could also be involved in the development of opioid tolerance in rats, the authors studied the antinociceptive effects of ibudilast and morphine in different models of coadministration.


METHODS
Antinociception was assessed using male Sprague- Dawley rats in hot plate and tail-flick tests. The effects of ibudilast on acute morphine-induced antinociception, induction of morphine tolerance, and established morphine tolerance were studied.


RESULTS
Systemic ibudilast produced modest dose-related antinociception and decreased locomotor activity at the studied doses of 2.5-22.5 mg/kg. The highest tested dose of 22.5 mg/kg produced 52% of the maximum possible effect in the tail-flick test. It had an additive antinociceptive effect when combined with systemic morphine. Coadministration of ibudilast with morphine did not attenuate the development of morphine tolerance. However, in morphine-tolerant rats, ibudilast partly restored morphine-induced antinociception.


CONCLUSIONS
Ibudilast produces modest antinociception, and it is effective in restoring but not in preventing morphine tolerance. The mechanisms of the effects of ibudilast should be better understood before it is considered for clinical use.
Lilius
Tuomas O
TO
Department of Pharmacology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
Rauhala
Pekka V
PV
Kambur
Oleg
O
Kalso
Eija A
EA
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D007212:Indolizines; D011720:Pyrazoles
D000701:Analgesics, Opioid; D009020:Morphine; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles