Mu-opioid receptors are not necessary for nortriptyline treatment of neuropathic allodynia.
Tricyclic antidepressants (TCAs) are among the first line treatments clinically recommended against neuropathic pain. However, the mechanism by which they alleviate pain is still unclear. Pharmacological and genetic approaches evidenced a critical role of delta-opioid receptors (DORs) in the therapeutic action of chronic TCA treatment. It is however unclear whether mu-opioid receptors (MORs) are also necessary to the pain-relieving action of TCAs. The lack of highly selective MOR antagonists makes difficult to conclude based on pharmacological studies. In the present work, we thus used a genetic approach and compared mutant mice lacking MORs and their wild-type littermates. The neuropathy was induced by unilateral sciatic nerve cuffing. The threshold for mechanical response was evaluated using von Frey filaments. MOR-deficient mice displayed the same baseline for mechanical sensitivity as their wild-type littermates. After sciatic nerve cuffing, both wild-type and MOR-deficient mice displayed an ipsilateral mechanical allodynia. After about 10 days of treatment, nortriptyline suppressed this allodynia in both wild-type and MOR-deficient mice. MORs are thus not critical for nortriptyline action against neuropathic pain. An acute injection of the DOR antagonist naltrindole induced a relapse of neuropathic allodynia in both wild-type and MOR-deficient mice, thus confirming the critical role of DORs in nortriptyline action. Moreover, morphine induced an acute analgesia in control and in neuropathic wild-type mice, but was without effect in MOR-deficient mice. While MORs are crucial for morphine action, they are not critical for nortriptyline action. Our results highlight the functional difference between DORs and MORs in mechanisms of pain relief.
Bohren
Yohann
Y
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
Karavelic
Dzenan
D
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
Tessier
Luc-Henri
LH
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
Yalcin
Ipek
I
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
Gavériaux-Ruff
Claire
C
Université de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Kieffer
Brigitte L
BL
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Freund-Mercier
Marie-José
MJ
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
Barrot
Michel
M
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000627:therapeutic use; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009661:Nortriptyline / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*
D018759:Adrenergic Uptake Inhibitors; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D009020:Morphine; D009661:Nortriptyline; C055382:naltrindole