RT Journal Article
SR Electronic
T1 Painful Inflammation-Induced Increase in μ-Opioid Receptor Binding and G-Protein Coupling in Primary Afferent Neurons
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 202
OP 210
DO 10.1124/mol.64.2.202
VO 64
IS 2
A1 C. Zöllner
A1 M. A. Shaqura
A1 C. P. Bopaiah
A1 S. Mousa
A1 C. Stein
A1 M. Schäfer
YR 2003
UL http://molpharm.aspetjournals.org/content/64/2/202.abstract
AB Opioids mediate their analgesic effects by activating μ-opioid receptors (MOR) not only within the central nervous system but also on peripheral sensory neurons. The peripheral analgesic effects of opioids are best described under inflammatory conditions (e.g., arthritis). The present study investigated the effects of inflammation on MOR binding and G-protein coupling of full versus partial MOR agonists in dorsal root ganglia (DRG) of primary afferent neurons. Our results show that Freund's complete adjuvant (FCA) unilateral hindpaw inflammation induces a significant up-regulation of MOR binding sites (25 to 47 fmol/mg of protein) on DRG membranes without affecting the affinity of either full or partial MOR agonists. In our immunohistochemical studies, the number of MOR-immunoreactive neurons consistently increased. This increase was mostly caused by small-diameter nociceptive DRG neurons. The full agonist DAMGO induced MOR G-protein coupling in DRG of animals without FCA inflammation (EC50 = 56 nM; relative Emax = 100%). FCA inflammation resulted in significant increases in DAMGO-induced MOR G-protein coupling (EC50 = 29 nM; relative Emax = 145%). The partial agonist buprenorphine hydrochloride (BUP) showed no detectable G-protein coupling in DRG of animals without FCA inflammation; however, partial agonist activity of BUP-induced MOR G-protein coupling was detectable in animals with FCA inflammation (EC50 = 1.6 nM; relative Emax = 82%). In behavioral studies, administration of BUP produced significant antinociception only in inflamed but not in noninflamed paws. These findings show that inflammation causes changes in MOR binding and G-protein coupling in primary afferent neurons. They further underscore the important differences in clinical studies testing peripherally active opioids in inflammatory painful conditions.