enkephalin--ala(2)-mephe(4)-gly(5)- and Constipation

Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund's Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain.

Topics: Analgesia; Analgesics, Opioid; Animals; Constipation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Gene Deletion; Gene Expression; Gene Knockout Techniques; Gene Order; Gene Targeting; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Knockout; Morphine; NAV1.8 Voltage-Gated Sodium Channel; Nociception; Pain; Pain Measurement; Posterior Horn Cells; Protein Binding; Receptors, Opioid, mu; Sensory Thresholds

To study the effects of mu and kappa opioid receptor agonists and antagonists on the isolated colon strips of rats with cathartic colon.. Cathartic colon model was established by feeding rats with contact laxatives, and effects of mu and kappa opioid receptor agonists and antagonists on electricity-stimulated contraction of isolated colon strips of rats with cathartic colon were observed.. Compared with control group, exogenous mu and kappa agonists inhibited significantly electricity-stimulated contraction of strips of cathartic colon (8.50+/-0.89 mm, 6.24+/-0.91 mm, 3.35+/-0.6 mm vs 11.40+/-0.21 mm P<0.01; 8.98+/-0.69 mm, 6.89+/-0.71 mm, 4.43+/-0.99 mm vs 11.40+/-0.21 mm, P<0.01). In contrast, the exogenous mu antagonist significantly enhanced electricity-stimulated contraction of isolated colon strips (13.18+/-0.93 mm, 15.87+/-0.98 mm, 19.46+/-1.79 mm vs 11.40+/-0.21 mm, P<0.01), but kappa antagonist had no effect on the isolated colon strips of rats with cathartic colon.. Mu and kappa opioid receptors are involved in the regulation of colon motility of rats with cathartic colon.

Topics: Analgesics, Opioid; Animals; Cathartics; Colon; Colonic Diseases, Functional; Constipation; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Gastrointestinal Motility; In Vitro Techniques; Male; Muscle Contraction; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Receptors, Opioid, kappa; Receptors, Opioid, mu