Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I2receptor agonist phenyzoline in adult male rats.
BACKGROUND
Emerging evidence suggests the potential utility of combining opioids with imidazoline I2receptor agonists for chronic pain. However, chronic pain management requires prolonged pharmacotherapy, and the consequence of such combination therapy remains unclear.


OBJECTIVE
This study examined the anti-hyperalgesic effect of the opioid oxycodone, the selective I2receptor agonist phenyzoline, alone and in combination, during prolonged treatment.


METHODS
Von Frey filament test was used to examine the anti-hyperalgesic effect of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain or chronic constriction injury (CCI)-induced neuropathic pain in rats. Twice-daily treatment with oxycodone and phenyzoline, alone or in combination, was continued until the development of significant tolerance (oxycodone) or as long as 19 days passed (phenyzoline).


RESULTS
In rats receiving CFA or CCI manipulation, mechanical hyperalgesia was dose-dependently reversed by oxycodone and phenyzoline. Twice-daily treatment with 2 × ED50dose of oxycodone for 7 days led to significant antinociceptive tolerance to oxycodone but not cross-tolerance to phenyzoline. Similarly, twice-daily treatment with 2 × ED50dose of phenyzoline for 19 days led to significant antinociceptive tolerance to phenyzoline but not cross-tolerance to oxycodone. Twice-daily treatment with the combined oxycodone and phenyzoline using different ratios (1:3, 1:1 and 3: 1) at the doses that were functionally equivalent to the treatment doses of oxycodone and phenyzoline for 13-19 days generally led to delayed antinociceptive tolerance.


CONCLUSIONS
Combination therapy with oxycodone and I2receptor agonists maintains prolonged antinociceptive effectiveness with reduced propensity to develop tolerance.
Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA.
David A
DA
Thorn
Research Triangle Institute, Research Triangle Park, NC, USA.
Yanan
Y
Zhang
Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA. junxuli@buffalo.edu.|Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NC, USA. junxuli@buffalo.edu.
Jun-Xu
JX
Li
D000700:Analgesics / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004361:Drug Tolerance / Q000502:physiology; D054755:Imidazoline Receptors / Q000819:agonists* / Q000502:physiology; D048288:Imidazolines / Q000008:administration & dosage*; D008297:Male; D010098:Oxycodone / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy* / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D000701:Analgesics, Opioid; D054755:Imidazoline Receptors; D048288:Imidazolines; C487767:imidazoline receptor 2; C000605851:phenyzoline; D010098:Oxycodone
Imidazoline I2 receptor; Oxycodone; Pain; Phenyzoline; Rats; Tolerance