Imidazoline I2 receptors: Target for new analgesics?

Pain remains a major clinical challenge because there are no effective analgesics for some pain conditions and the mainstay analgesics for severe pain, opioids, have serious unwanted effects. There is a dire need for novel analgesics in the clinic. Imidazoline receptors are a family of three receptors (I1, I2 and I3) that all can recognize compounds with an imidazoline structure. Accumulating evidence suggests that I2 receptors are involved in pain modulation. Ligands acting at I2 receptors are effective for tonic inflammatory and neuropathic pain but are much less effective for acute phasic pain. When studied in combination, I2 receptor ligands enhance the analgesic effects of opioids in both acute phasic and chronic tonic pain. During chronic use, patients can develop tolerance to and dependence on opioids. Imidazoline I2 receptor ligands can attenuate the development of tolerance to opioid analgesia and inhibit drug withdrawal or antagonist precipitation induced abstinence syndrome in animals. Taken together, drugs acting on I2 receptors may be useful as a monotherapy or combined with opioids as an adjuvant for treating pain. Future studies should focus on understanding the relative efficacy of I2 receptor ligands and developing new compounds to fill the gap in intrinsic efficacy continuum of I2 receptors.