Opioid receptors: toward separation of analgesic from undesirable effects

• Novel development strategies separate analgesic efficacy from opioid side effects.
• Targeting receptor splice variants or receptor heterodimers could exhibit high analgesic efficacy with minimal side effects.
• ‘Drug cocktails’ to alter receptor trafficking and antagonist-activated receptor mutants are other viable approaches to minimize side effects.
• Future drug designs should be guided by crystal structures of resolved receptors and in vivo consequences of biased agonism.

The use of opioid analgesics for pain has always been hampered by their many side effects; in particular, the addictive liability associated with chronic use. Recently, attempts to develop analgesic agents with reduced side effects have targeted either the putative opioid receptor splice variants or the receptor hetero-oligomers. This review discusses the potential for receptor splice variant- and the hetero-oligomer-based discovery of new opioid analgesics. We also examine an alternative approach of using receptor mutants for pain management. Finally, we discuss the role of the biased agonism observed and the recently reported opioid receptor crystal structures in guiding the future development of opioid analgesics.