The κ-opioid receptor in opioid dependence

Opioid dependence that particularly mediates through the μ-opioid receptor remains a major concern of opioid analgesics. Drugs which interact with κ-opioid receptors are increasingly used as an alternative to μ- agonist analgesic. Several studies have reported that chronic administration of κ-opioid agonists such as U-50488H, U-69,593, and butorphanol also results in development of physical dependence/withdrawal. In addition, the ability of a highly selective κ-opioid antagonist, nor-binaltorphimine, given systemically or spinally, to precipitate withdrawal behaviors in opioid-dependent animals further demonstrates that both supraspinal and spinal sites of κ-opioid receptors play an important role in opioid dependence/withdrawal. With regard to the role of glutamate in opioid dependence/withdrawal, the κ-opioid receptor located at the presynaptic nerve terminal within the locus coeruleus crucially regulates glutamate release during the expression of opioid withdrawal. Physical dependence on κ-opioid agonists is associated with the downregulation and antagonist- sensitive state of the κ-opioid receptor in the spinal cord and specific brain areas. However, alterations of the κ-opioid receptor may not completely explain the mechanisms of dependence development. With cloned κ- opioid receptors recently available, it could be elucidated that the cellular and biological mechanisms of κ-opioid receptors for the development of dependence/withdrawal may differ from those of μ-opioid receptors.