Mu opioid receptors on primary afferent nav1.8 neurons contribute to opiate-induced analgesia: insight from conditional knockout mice.
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.
IGBMC Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational Medicine and Neurogenetic Programme, UdS Université de Strasbourg, INSERM U964, CNRS UMR7104, Illkirch, France.
Raphaël
R
Weibel
David
D
Reiss
Laurie
L
Karchewski
Olivier
O
Gardon
Audrey
A
Matifas
Dominique
D
Filliol
Jérôme A J
JA
Becker
John N
JN
Wood
Brigitte L
BL
Kieffer
Claire
C
Gaveriaux-Ruff
D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003248:Constipation / Q000139:chemically induced; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D055786:Gene Knockout Techniques; D023061:Gene Order; D018390:Gene Targeting; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000188:drug therapy / Q000235:genetics; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D012684:Sensory Thresholds / Q000187:drug effects
D000701:Analgesics, Opioid; D062559:NAV1.8 Voltage-Gated Sodium Channel; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine