Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide

Abstract

Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G-protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G.

Novel neuroactive steroid with hypnotic and T‐type calcium channel blocking properties exerts effective analgesia in a rodent model of post‐surgical pain

“…However, clinical application of morphine is often restricted due to known problems such as tolerance, addiction and opioid‐induced hyperalgesia. Roeckel et al () have shown that morphine induces tolerance and hyperalgesia in wild type, but not in μ‐opioid receptor KO mice, suggesting that opioid induced hyperalgesia likely occurs via the similar mechanism that provides beneficial analgesic effects. In contrast, we did not notice hyperalgesia occurrence after repetitive application of 3β‐OH.…”

Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

“…However, the lack of antinociceptive role of MOP in chronic pain models is not described here for the first time. Indeed, constitutive MOP knockouts failed to show enhanced hypersensitivity in response to tissue or nerve injury (Bohren et al, ; Gavériaux‐Ruff et al, ; Mansikka et al, ; Roeckel et al, ). In agreement with the pronociceptive effects of MOP, repeated MOP stimulation has been associated with opioid‐induced hyperalgesia and reduced opioid antinociception in models of inflammatory and neuropathic pain (Roeckel, Le Coz, Gavériaux‐Ruff, & Simonin, ).…”

“…In agreement with the pronociceptive effects of MOP, repeated MOP stimulation has been associated with opioid‐induced hyperalgesia and reduced opioid antinociception in models of inflammatory and neuropathic pain (Roeckel, Le Coz, Gavériaux‐Ruff, & Simonin, ). In addition, full MOP knockouts failed to develop hyperalgesia after repeated morphine treatment (Corder et al, ; Roeckel et al, ), suggesting MOP implication in this morphine‐induced detrimental effect. Our results with Nav1.8‐MOP knockouts show lack of pronociceptive effects of MOP expressed in sensory neurons, in contrast to the previously described involvement of peripheral MOP in opioid‐induced pronociception (Corder et al, ).…”

Impact of sex on pain and opioid analgesia: a review

“…M3G binds to microglial TLR4 to produce hyperalgesia and allodynia (pain response from non-noxious stimuli) (Due et al, 2012), whereas M6G binds to MOR to produce potent pain inhibition (Wittwer and Kern, 2006; see Figure 3). Pharmacological studies show that administration of M3G correlates with nociception (Smith and Smith, 1995) and that M3G actively opposes opioid analgesia, as well as the analgesic effects of M6G (Ekblom et al., 1993; Roeckel et al, 2017;Doyle and Murphy, 2018). …”