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Imidazoline I2 receptors: An update.

ABSTRACT: Since first introduced more than two decades ago, the research in imidazoline I2 receptors has been steadily increasing. This review provides an update on the current status of I2 receptor pharmacology. Imidazoline I2 receptors or I2 binding sites refer to several (at least four) different proteins that bind to [3H]-idazoxan and [3H]-2-BFI with high affinity. The molecular identities of the proteins remain elusive. One of the proteins (45kD) seems to be consistent with the identity of brain creatine kinase. The biological functions of I2 receptors have been primarily unveiled by the studies of selective I2 receptor ligands. Accumulating evidence suggests that I2 receptor ligands are effective analgesics for persistent and chronic painful conditions such as inflammatory, neuropathic and postoperative pain. One selective I2 receptor ligand, CR4056, has been advanced to phase II clinical trial with the therapeutic indication of chronic inflammatory pain (osteoarthritis). The expansion to the treatment of other chronic pain conditions should be expected if CR4056 could eventually be approved as a new drug. I2 receptor ligands also demonstrate robust discriminative stimulus activity and induce a characteristic discriminative cue in animals. Biochemical and preclinical in vivo investigations also suggest that I2 receptor ligands have neuroprotective activity and modulate body temperature. The emerging discrepancies of a range of purported selective I2 receptor ligands suggest different pharmacological effects mediated by discrete I2 receptor components which likely attribute to the I2 receptor-related proteins. It is proposed that the I2 receptors represent an emerging drug target for the treatment of neurological disorders such as pain and stroke, and deserve more research attention to translate preclinical findings to pharmacotherapies.

SUBMITTER: Li JX

PROVIDER: S-EPMC5600648 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Imidazoline I2 receptors: An update.

Li Jun-Xu JX

Pharmacology & therapeutics 20170316

Since first introduced more than two decades ago, the research in imidazoline I2 receptors has been steadily increasing. This review provides an update on the current status of I2 receptor pharmacology. Imidazoline I2 receptors or I2 binding sites refer to several (at least four) different proteins that bind to [3H]-idazoxan and [3H]-2-BFI with high affinity. The molecular identities of the proteins remain elusive. One of the prot ...[more]

PMID: 28322973

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Project description:Background and purposeAlthough the antinociceptive efficacies of imidazoline I2 receptor agonists have been established, the exact post-receptor mechanisms remain unknown. This study tested the hypothesis that monoaminergic transmission is critical for I2 receptor agonist-induced antinociception.Experimental approachvon Frey filaments were used to assess antinociceptive effects of two I2 receptor agonists, 2-BFI and CR4056 on chronic constriction injury (CCI)-induced neuropathic pain or complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Rectal temperature was measured to assess hypothermic effects of 2-BFI. A two-lever drug discrimination paradigm in which rats were trained to discriminate 5.6 mg·kg-1 2-BFI (i.p.) from its vehicle was used to examine the discriminative stimulus effects of 2-BFI. In each experiment, pharmacological mechanisms were investigated by combining 2-BFI or CR4056 with various pharmacological manipulations of the monoaminergic system including selective reuptake inhibition, monoamine depletion and monoamine receptor antagonism.Key resultsIn the CCI model, selective reuptake inhibitors of 5-HT (fluoxetine) or noradrenaline (desipramine), but not dopamine (GBR12909), enhanced 2-BFI-induced antinociception. Selective depletion of 5-HT or noradrenaline almost abolished 2-BFI-induced antinociception. 5-HT1A , 5-HT2A and α1 -adrenoceptor antagonists, but not other monoaminergic antagonists, attenuated 2-BFI and CR4056-induced antinociception in CCI and/or CFA models. However, none of these monoamine receptor antagonists significantly altered 2-BFI-induced hypothermia or discriminative stimulus effects.Conclusions and implicationsAntinociception induced by I2 receptor agonists was mediated by serotonergic and noradrenergic mechanisms with 5-HT1A , 5-HT2A and α1 -adrenoceptor being particularly important. In contrast, the hypothermic and discriminative stimulus effects of I2 receptor agonists were mediated by distinct, independent mechanisms.

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Imidazoline I2 receptors: An update.

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Imidazoline I<sub>2</sub> receptors: An update.

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