Morphine-3-glucuronide causes antinociceptive cross-tolerance to morphine and increases spinal substance P expression

Blomqvist, Kim; Viisanen, Hanna; Ahlström, Fredrik; Jokinen, Viljami; Sidorova, Yulia; Suleymanova, Ilida; Rauhala, Pekka; Kalso, Eija; Lilius, Tuomas

doi:10.1016/j.ejphar.2020.173021

Cited by 10 publications

(11 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“… Doyle and Murphy (2018) reported higher levels of M3G following morphine administration in female rats than in male rats. M3G exerts no analgesic effects per se , but it induces hyperalgesia in mice when administered alone ( Juni et al, 2006 ; Roeckel et al, 2017 ; Blomqvist et al, 2020 ). Thus, higher levels of M3G in females may explain the lower analgesic potency of heroin in female rats but not their greater resistance to hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

Marchette

Gregory-Flores

Tunstall

et al. 2021

Neurobiology of Stress

View full text Add to dashboard Cite

Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hyperalgesia remains to be determined. We hypothesized that KOR antagonism would reverse opioid withdrawal-induced hyperalgesia in opioid-dependent rats. Male and female Wistar rats received daily injections of heroin (2–6 mg/kg, SC) and were tested for mechanical sensitivity in the electronic von Frey test 4–6 h into withdrawal. Female rats required significantly more heroin than male rats to reach comparable levels of both heroin-induced analgesia and hyperalgesia (6 mg/kg vs. 2 mg/kg). Once hyperalgesia was established, we tested the effects of the KOR antagonists nor-binaltorphimine (norBNI; 30 mg/kg, SC) and 5′-guanidinonaltrindole (5′GNTI; 30 mg/kg, SC). When the animals continued to receive their daily heroin treatment (or saline treatment in the repeated saline group) five times per week throughout the experiment, both KOR antagonists reversed heroin withdrawal-induced hyperalgesia. The anti-hyperalgesia effect of norBNI was more prolonged in males than in females (14 days vs. 7 days), whereas 5′GNTI had more prolonged effects in females than in males (14 days vs. 4 days). The behavioral effects of 5′GNTI coincided with higher 5′GNTI levels in the brain than in plasma when measured at 24 h, whereas 5′GNTI did not reverse hyperalgesia at 30 min posttreatment when 5′GNTI levels were higher in plasma than in the brain. Finally, we tested the effects of 5′GNTI on naloxone-induced and spontaneous signs of opioid withdrawal and found no effect in either male or female rats. These findings indicate a functional role for KORs in heroin withdrawal-induced hyperalgesia that is observed in rats of both sexes.

show abstract

Section: Discussionmentioning

confidence: 99%

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

Marchette

Gregory-Flores

Tunstall

et al. 2021

Neurobiology of Stress

View full text Add to dashboard Cite

show abstract

“…According to Schaefer et al, the estimated total annual costs of neuropathic pain were equal to 27,259 USD per patient [ 85 ]. Neuropathic pain can appear as a result of traumatic nerve lesion, disease e.g., diabetes, viral infection, cancer or as a side effect or treatment with e.g., anticancer drugs or opioids [ 86 , 87 ], and it is more common in women and the elderly [ 86 ]. Thus, due to an increase in the prevalence of underlying conditions and aging population, the number of affected people is expected to grow in the future.…”

Section: Role Of Ret In Various Disease Statesmentioning

confidence: 99%

RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer

Mahato

Sidorova

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Rearranged during transfection (RET) is the tyrosine kinase receptor that under normal circumstances interacts with ligand at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism. RET plays a pivotal role in the development of both peripheral and central nervous systems. RET is expressed from early stages of embryogenesis and remains expressed throughout all life stages. Mutations either activating or inhibiting RET result in several aggressive diseases, namely cancer and Hirschsprung disease. However, the physiological ligand-dependent activation of RET receptor is important for the survival and maintenance of several neuronal populations, appetite, and weight gain control, thus providing an opportunity for the development of disease-modifying therapeutics against neurodegeneration and obesity. In this review, we describe the structure of RET, its signaling, and its role in both normal conditions as well as in several disorders. We highlight the differences in the signaling and outcomes of constitutive and ligand-induced RET activation. Finally, we review the data on recently developed small molecular weight RET agonists and their potential for the treatment of various diseases.

show abstract

“…In rodents, i.p., s.c. and i.t. injections of M3G alone clearly induce thermal hyperalgesia and mechanical allodynia ( Juni et al, 2006 ; Komatsu et al, 2009 , 2016 ; Lewis et al, 2010 ; Due et al, 2012 ; Arout et al, 2014 ; Allette et al, 2017 ; Roeckel et al, 2017 ; Blomqvist et al, 2020 ). Additionally, morphine and M6G analgesic effects are markedly reduced by M3G ( Smith et al, 1990 ; Qian-Ling et al, 1992 ; Ekblom et al, 1993 ; Faura et al, 1996 , 1997 ; Gardmark et al, 1998 ).…”

Section: Morphine-3-glucuronidementioning

confidence: 99%

“…Similar observations were made in the extracellular cortical fluid following s.c. administration of morphine ( Barjavel et al, 1995 ). Consequently, M3G was proposed to counteract morphine-induced analgesia and to produce neuroexcitatory effects responsible for some morphine side effects ( Gong et al, 1991 ; Smith and Smith, 1995 ; Faura et al, 1997 ; Roeckel et al, 2017 ; Blomqvist et al, 2020 ).…”

Section: Morphine-3-glucuronidementioning

confidence: 99%

“…For instance, a recent study revealed that antinociceptive tolerance was prevented in TLR2 and TLR4 null mutants, but not in MyD88 –/– animals ( Thomas et al, 2022 ). Since several studies suggested that TLR4 could be the receptor mediating M3G effects, M3G has been proposed to play a role in morphine side effects, especially in antinociceptive tolerance ( Juni et al, 2006 ; Blomqvist et al, 2020 ). However, one should note that two studies invalidate the implication of TLR4 in morphine’s effects ( Fukagawa et al, 2013 ; Mattioli et al, 2014 ).…”

Section: Morphine-3-glucuronidementioning

confidence: 99%

See 1 more Smart Citation

Morphine-3-Glucuronide, Physiology and Behavior

Gabel

Hovhannisyan

Berkati

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Morphine remains the gold standard painkiller available to date to relieve severe pain. Morphine metabolism leads to the production of two predominant metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). This metabolism involves uridine 5′-diphospho-glucuronosyltransferases (UGTs), which catalyze the addition of a glucuronide moiety onto the C3 or C6 position of morphine. Interestingly, M3G and M6G have been shown to be biologically active. On the one hand, M6G produces potent analgesia in rodents and humans. On the other hand, M3G provokes a state of strong excitation in rodents, characterized by thermal hyperalgesia and tactile allodynia. Its coadministration with morphine or M6G also reduces the resulting analgesia. Although these behavioral effects show quite consistency in rodents, M3G effects are much more debated in humans and the identity of the receptor(s) on which M3G acts remains unclear. Indeed, M3G has little affinity for mu opioid receptor (MOR) (on which morphine binds) and its effects are retained in the presence of naloxone or naltrexone, two non-selective MOR antagonists. Paradoxically, MOR seems to be essential to M3G effects. In contrast, several studies proposed that TLR4 could mediate M3G effects since this receptor also appears to be essential to M3G-induced hyperalgesia. This review summarizes M3G’s behavioral effects and potential targets in the central nervous system, as well as the mechanisms by which it might oppose analgesia.

show abstract

Morphine-3-glucuronide causes antinociceptive cross-tolerance to morphine and increases spinal substance P expression

Cited by 10 publications

References 37 publications

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer

Morphine-3-Glucuronide, Physiology and Behavior

Contact Info

Product

Resources

About