Anti-hyperalgesic effects of imidazoline I2 receptor ligands in a rat model of inflammatory pain: interactions with oxycodone

Abstract

Rationale Emerging preclinical evidence suggests that imidazoline I2 receptor ligands may be effective analgesics. Quantitative analysis of the combined I2 receptor ligands and opioids is needed for the justification of combination therapy. Objective This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats. Methods Von Frey filament test was used to examine the anti-hyperalgesic effects of drugs in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. Schedule-controlled responding was used to assess the rate-altering effects of study drugs. Duration of actions of individual drugs (2-BFI, phenyzoline and oxycodone) alone or in combination were studied. Dose-addition analysis was employed to assess the anti-hyperalgesic interactions between drugs. Results Oxycodone (0.1-3.2 mg/kg, i.p.), 2-BFI (1-17.8 mg/kg, i.p.) and phenyzoline (17.8-56 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and oxycodone produced additive interactions while phenyzoline and oxycodone produced supra-additive interactions under all fixed ratios. The same drug combinations did not alter or significantly reduced the operant responding depending on the ratios of the drug combinations. Conclusions Quantitative analysis of the anti-hyperalgesic effects of I2 receptor ligands strongly supports the therapeutic potential of I2 receptor ligands against inflammatory pain. In addition, the data reveal that phenyzoline is superior to the prototypic I2 receptor ligand 2-BFI for the management of pain and warrants further consideration as a novel analgesic.

Antinociceptive Interactions between the Imidazoline I2 Receptor Agonist 2-BFI and Opioids in Rats: Role of Efficacy at the -Opioid Receptor

“…The interactions between 2-BFI and fentanyl in the mechanical nociception and schedule-controlled responding assays of the present study largely agree with previous reports, in which 2-BFI combined with morphine or oxycodone reversed CFA-induced mechanical nociception in a simple additive manner (Li et al, 2014;Thorn et al, 2015). The additive to infra-additive interactions between 2-BFI and fentanyl in the thermal nociception test were somewhat unexpected, although comparable interactions had not been previously examined for thermal nociception.…”

“…CFA injection into the right hindpaw of rats produced mechanical and thermal hyperalgesia that persisted well beyond the duration of the experiments of this study as described previously (Li et al, 2014;Thorn et al, 2015). Mean pre-CFA baseline values (6S.E.M.)…”

“…Previous investigations of analgesic drug combinations involving I 2 R ligands have focused on high-efficacy m-opioids and have found additive to supra-additive interactions that appear to be dependent on the I 2 R ligand (Lanza et al, 2014;Thorn et al, 2015) or the behavioral tests (Li et al, 2011b(Li et al, , 2014. The interactions between 2-BFI and fentanyl in the mechanical nociception and schedule-controlled responding assays of the present study largely agree with previous reports, in which 2-BFI combined with morphine or oxycodone reversed CFA-induced mechanical nociception in a simple additive manner (Li et al, 2014;Thorn et al, 2015).…”

“…The level of anesthesia was assessed by the loss of righting reflex. Since neither the course of hyperalgesia nor repeated treatment affects results (Li et al, 2014;Thorn et al, 2015), mechanical nociception tests were conducted 24 hours after CFA inoculation, and thermal nociception tests were conducted after an additional 24 hours (total of 48 hours post-CFA). In Figs.…”

“…Many recent preclinical studies have established the imidazoline I 2 receptor (I 2 R) as a promising target to treat chronic pain, both as monotherapy and when combined with m-opioids (Ferrari et al, 2011;Lanza et al, 2014;Li et al, 2014;Thorn et al, 2015). The ability of I 2 R ligands to enhance m-opioid agonist-induced analgesia in acute pain models, whereas these drugs alone do not produce antinociception (Li et al, 2011b;Thorn et al, 2011;Sampson et al, 2012), demonstrates a unique relationship between these two receptor systems.…”