Mu‐opioid receptors are not necessary for nortriptyline treatment of neuropathic allodynia

Abstract

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.

The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice

“…It allowed demonstration that glial activation and a central shift in neuronal anion gradient participate in changes in the activity and in the responses of spinal nociceptive neurons and in neuropathic allodynia 24,[36][37][38] . The influence of glutamate receptors 7,[39][40][41] , of opioid receptors 16,[42][43][44][45] and of nicotinic receptors 46 was also studied in this model.…”

“…Similar to clinical observations: gabapentinoids display both an acute short-lasting analgesic action at high dose and a delayed sustained relieving action that is observed after a few days of treatment, tricyclic antidepressants and selective serotonin and noradrenaline reuptake inhibitors have no acute analgesic effect at relevant dose but they display a delayed sustained relieving action that requires 1 to 2 weeks of treatment, and the selective serotonin reuptake inhibitor fluoxetine is ineffective 16 . The model is thus appropriate to study the molecular mechanism underlying these treatments [16][17][18]44,45,47 , which may reveal new therapeutic targets to test in patients [48][49][50][51] .…”

“…The possibility to use genetically modified animals 17,18,[44][45][46][47]52 , the long-lasting allodynia, the response to clinically used treatments and the time-dependent development of anxiodepressive symptoms make this model appropriate for the study of the various aspects and consequences of neuropathic pain and its treatments, which have already brought valuable information to this field of research.…”

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain

“…TCAs alleviate allodynic effects in a neuropathic pain model; however, in DOR-knockout mice, the efficacy of these drugs was reduced [95]. Antidepressant drugs are still effective in MOR-knockout animals, suggesting that these drugs are regulated by DOR rather than MOR [96]. KORs are also not necessary for the effect of TCAs against neuropathic allodynia.…”

Antidepressant Drugs and Pain

“…Indeed, several studies have suggested that this action may be centrally mediated, e.g., via noradrenergic descending pathways. The generation of mice lacking μ- (Bohren et al, 2010) and δ-opioid receptors (Benbouzid et al, 2008b) has provided a novel approach to analyse the relationship between antidepressant activity and opioid signalling. Chronic treatment with the TCA nortriptyline induces antiallodynic effects in neuropathic wild-type and δ-opioid KO mice (Benbouzid et al, 2008b;Bohren et al, 2010), but not in μ-opioid deficient mice (Bohren et al, 2010), indicating that μ-opioid receptors are not required for the analgesic effects of nortriptyline in neuropathic pain.…”