Behavioral characterization of imidazoline I2 receptor ligands: Interactions with opioids

Chronic pain affects > 30% of the US population and currently available analgesics are not adequate to meet the clinical needs. Opioids are effective for treating moderate to severe pain; however, their use is limited due to the unwanted effects, such as constipation, physical dependence, abuse and overdose. Thus, there is a dire clinical need to develop novel and effective analgesics.;The imidazoline I2 receptor is an emerging drug target for analgesics as I2 receptor ligands demonstrate antinociceptive effects in rodent models of acute and chronic pain and also enhance the antinociceptive effects of morphine. These findings suggest that I2 receptor ligands may be effective alone or in combination with opioids to treat pain. However, there are several gaps in the literature that need to be addressed. Firstly, there currently exists no in vivo bioassay to characterize I2 receptor ligands. Secondly, although several studies demonstrate that I2 receptor ligands enhance the antinociceptive effects of morphine, it remains unclear whether they also modulate the effects of other opioids. Lastly, little is known of the effects of I2 receptor ligands on the unwanted effects of opioids, particularly the development of tolerance and dependence.;We aimed to fill these gaps in the literature to shed light on the true clinical potential these compounds. We found that selective I2 receptor ligands consistently and dose-dependently decrease the body temperature in rats, and the effects were mediated by I2 receptors. Therefore, this offers a validated and simple in vivo assay for understanding the neuropharmacology of the I2 receptor system and facilitating the development of new I2 receptor ligands.;Next, we found that I2 receptor ligands produced antinociceptive effects in a rat model of tonic persistent pain and these effects appear to be acting through a centrally- but not peripherally-mediated mechanism. In addition, the non-selective I2 receptor ligand agmatine and the selective I2 receptor ligand 2-BFI enhanced the antinociceptive effects of the opioids morphine and tramadol in a warm water tail withdrawal procedure. Furthermore, the selective I2 receptor ligands, 2-BFI and phenyzoline, enhanced the antinociceptive effects of oxycodone in a rat model of chronic pain. Interestingly, phenyzoline produced a synergistic interaction with oxycodone, while 2-BFI produced an additive interaction. Lastly, we established that the selective I2 receptor ligand 2-BFI significantly attenuated the development of tolerance to the rate suppressing effects of morphine as well as the development of physical dependence to morphine. In addition, the selective I2 receptor ligands 2-BFI, BU224 and CR4056 also attenuated the development of tolerance to the antinociceptive effects of morphine. These results further support that opioids combined with imidazoline I2 receptor ligands may be a clinically effective combination therapy to treat pain with concurrent reduction in the unwanted effects associated with repeated opioid use. Overall, these studies strongly support the clinical potential of targeting the imidazoline I2 receptor for pain treatment. I 2 receptor ligands may provide invaluable utility as a monotherapy or combination therapy with opioids to alleviate many painful conditions.