Relative contributions of peripheral versus supraspinal or spinal opioid receptors to the antinociception of systemic opioids.

The contribution of supraspinal, spinal or peripheral mu-opioid receptors (MORs) to the overall antinociception of systemic centrally penetrating versus peripherally restricted opioids has not been thoroughly investigated. Therefore, we examined paw pressure thresholds in Wistar rats with complete Freund's adjuvant hindpaw inflammation following different doses of intraplantar (i.pl.) as well as intravenous (i.v.) fentanyl (6.25-50 μg/kg), morphine (1-7.5 mg/kg) or loperamide (1-7.5 mg/kg). Antagonism of the i.v. mu-opioid agonists by intracerebroventricular (i.c.v.), intrathecal (i.t.) or i.pl. naloxone-methiodide (NLXM) revealed the relative contributions of supraspinal, spinal and peripheral MOR to the overall antinociceptive effects. In parallel, the MOR density at these three levels of pain transmission was assessed by radioligand binding. Antinociceptive effects of i.v. fentanyl and morphine, but not of the peripherally restricted loperamide were two- to threefold greater and longer lasting compared with their i.pl. administration. I.c.v. but not i.pl. NLXM significantly antagonized fentanyl's and morphine's antinociception by 70-80%, whereas i.t. NLXM reduced it by 20-30%. In contrast, antinociception of i.v. loperamide was abolished by i.pl. but not by i.c.v. or i.t. NLXM. In parallel, a respective 32- and sixfold higher MOR density in supraspinal and spinal versus peripheral sensory neurons was detected. In conclusion, in comparison with supraspinal and spinal opioid receptors, peripheral opioid receptors do not significantly contribute to the antinociception of systemic fentanyl and morphine during inflammatory pain. Antinociception of their i.v. administration was superior over both i.v and i.pl. loperamide, acting exclusively via peripheral MOR. These findings may guide the future development of novel peripherally restricted opioids.