Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I2 receptor agonist phenyzoline in adult male rats

Abstract

Rationale Emerging evidence suggests the potential utility of combining opioids with imidazoline I2 receptor 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 I2 receptor 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 × ED50 dose of oxycodone for 7 days led to significant antinociceptive tolerance to oxycodone but not cross-tolerance to phenyzoline. Similarly, twice daily treatment with 2 × ED50 dose 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 I2 receptor agonists maintains prolonged antinociceptive effectiveness with reduced propensity to develop tolerance.

Imidazoline I 2 receptors: An update

“…In a complete Freund’s adjuvant (CFA)-induced inflammatory pain model, three selective I 2 receptor ligands (2-BFI, BU224 and tracizoline) all dose-dependently and significantly reduced the mechanical and thermal hyperalgesia (Li, Thorn, Qiu, Peng, & Zhang, 2014). 2-BFI and the I 2 receptor ligand phenyzoline also reduced mechanical hyperalgesia in rats that received chronic constriction injury (CCI), a model of peripheral neuropathic pain (Li et al, 2014; Thorn, Zhang, & Li, 2017). The anti-hyperalgesic effect of 2-BFI was attenuated by idazoxan, confirming I 2 receptor mediated mechanism (Li et al, 2014).…”

“…However, doses higher than 20 mg/kg did develop antinociceptive tolerance after two weeks, a process that was substantially slower than that during buprenorphine treatment (Meregalli et al, 2012). We recently found that twice-daily treatment with phenyzoline at the dose that produced near maximal antinociceptive effect in the CFA and CCI rat chronic pain models for 19 days only produced a slight although significant antinociceptive tolerance (Thorn, Zhang, & Li, 2017). As a comparison, oxycodone produced dramatic tolerance to its antinociceptive effect under similar treatment conditions (Thorn, Zhang, & Li, 2017).…”

“…We recently found that twice-daily treatment with phenyzoline at the dose that produced near maximal antinociceptive effect in the CFA and CCI rat chronic pain models for 19 days only produced a slight although significant antinociceptive tolerance (Thorn, Zhang, & Li, 2017). As a comparison, oxycodone produced dramatic tolerance to its antinociceptive effect under similar treatment conditions (Thorn, Zhang, & Li, 2017). Combined, the results suggest that the process of tolerance development is slow, if at all, as long as the dose used is limited to therapeutically relevant dose.…”

“…Indeed, an earlier study found that I 2 receptor ligands reduced the antinociceptive tolerance to morphine in an acute nociception assay (radiant heat tail flick) (Boronat, Olmos, & Garcia-Sevilla, 1998). We recently found that the combination of phenyzoline and oxycodone developed less antinociceptive tolerance and the tolerance developed at a much slower rate as compared to oxycodone alone in both CFA-treated and CCI rats (Thorn, Zhang, & Li, 2017). …”

Antinociceptive Effects of Isosakuranetin in a Rat Model of Peripheral Neuropathy

“…For the dose-effect functions of isosakuranetin, the data at time 30-min post-injection were converted to percentage of maximal possible effect using the following formula: % maximal possible effect = (post-drug value for a behavioral response [g or s] - pre-drug value for a behavioral response/[presurgery baseline value - pre-drug value for a behavioral response] × 100). The ED 50 values and 95% confidence limits (CLs) of isosakuranetin in the different measures were determined by linear regression using the portion of the dose-effect curve spanning 50% as previously described [17]. For the rotarod test, data were analyzed with one-way ANOVA followed by post hoc Bonferroni test.…”