Determinants of opioid abuse potential: Insights using intracranial self-stimulation

Intracranial self-stimulation (ICSS) is one procedure that can be used for preclinical abuse potential assessment. In ICSS procedures, subjects with microelectrodes implanted into a brain-reward region are trained to press an operant response lever for pulses of electrical brain stimulation, and drugs are evaluated for their effectiveness to increase or "facilitate" ICSS responding (an abuse-related effect) or to depress ICSS responding (an abuse-limiting effect). ICSS has been used for decades to evaluate determinants of opioid abuse potential, and this article reviews pharmacological and biological determinants of opioid abuse potential as revealed by ICSS studies in rodents. One of the most important observations from ICSS studies is that abused mu opioid receptor (MOR) agonists like morphine often fail to produce abuse-related ICSS facilitation in opioid-naïve subjects, but several days of repeated opioid exposure is sufficient for opioid-induced facilitation to emerge. Future studies with ICSS could help (a) to clarify mechanisms that increase MOR agonist abuse potential during early opioid exposure or during chronic exposure leading to dependence, (b) to evaluate novel opioids either developed as candidate analgesics with reduced abuse potential or identified as designer opioids being synthesized and distributed for illicit use, and (c) to test candidate pharmacotherapies for treatment of opioid abuse in non-dependent and dependent subjects.