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CNS Receptors for Opioids
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Richard J. Knopp, Mary Hunt, James K. Wamsley, Henry I. Yamamura
The volume of evidence supporting the positive effect on behavioral reinforcement mediated by the μ opioid receptor contrasts to the limited number of studies exploring the role of δ opioid receptors. The availability of DPDPE has provided a means of studying δ opioid receptor involvement in opioid-induced reward. One paradigm used to investigate drug-induced reward effects is to measure the facilitation of electrical self-stimulation. Jenck et al. (1987) examined the abilities of morphine and selective δ (DPDPE) and κ (U-50,488H) opioid agonists to facilitate brain stimulation reward after ventral tegmental injection. Both morphine and DPDPE showed such facilitation while U-50,488H did not. Conditioned place preference studies give more evidence for δ opioid receptor-mediated reinforcement. DPDPE (10 to 25 μg/animal) and morphine (10 μg/animal) given by i.c.v. injection to rats produced a preference for the drug administration side of a shuttle box (Shippenberg et al., 1987). The preference induced by DPDPE was antagonized by the selective δ opioid antagonist, ICI 174,864 while that produced by morphine was not. These two studies suggest that δ, like μ opioid receptors, may also mediate behavioral reward.
The brain heme oxygenase/biliverdin reductase system as a target in drug research and development
Published in Expert Opinion on Therapeutic Targets, 2022
Heme oxygenase-1 is also a target for opioid drugs. In a diabetic mice model induced by the injection of streptozotocin, the administration of the HO-1 inducer Co-PP-IX (10 mg/kg intraperitoneally for 5 days) fully counteracted the mechanical and thermal hypersensitivity caused by diabetes [123]. These beneficial effects correlated with the overexpression of HO-1 in spinal cord, dorsal root ganglia and sciatic nerve samples [123]. Interestingly, in this preclinical model of diabetes mellitus, Co-PP-IX potentiated the mechanical antiallodynic, thermal antihyperalgesic and thermal antiallodynic effects produced by low-dose morphine (0.5 mg/kg) [123]. The active involvement of HO-1 on these morphine-induced antinociceptive effects were confirmed by the evidence that the administration of the HO inhibitor Sn-PP-IX (10 mg/kg intraperitoneally) cured them [123]. Finally, Co-PP-IX strengthened the antinociceptive effects of morphine by increasing the expression of opioid µ receptor in the spinal cord [123]. In the streptozotocin-treated mice, Co-PP-IX potentiated the antinociceptive effects of the δ opioid receptor agonist [d-Pen(2), d-Pen(5)]-Enkephalin with a mechanism involving the HO-1-induced generation of CO [124]. In an inflammatory pain model, such as the carrageenan model, HO-1-derived CO has been shown to produce antinociceptive effects through the activation of ATP-sensitive K+ channels [125].
What ketamine can teach us about the opioid system in depression?
Published in Expert Opinion on Drug Discovery, 2020
Laura Perez-Caballero, Victor Perez, Esther Berrocoso
Additionally, preclinical assays demonstrated that MOR and δ-opioid receptor activation and/or κ-opioid receptor blockade produces antidepressant-like effects in animal models of depression [24]. Accordingly, evidence has accumulated that severe and recurrent depression can be alleviated by multimodal opioid-based compounds [25]. However, the risk of abuse and dependence on these drugs has discouraged their use to treat depressed patients. Currently, buprenorphine offers the greatest promise as a drug to treat MDD. Buprenorphine is a partial MOR agonist and κ-opioid receptor antagonist, and it is an opioid medication commonly prescribed to treat opioid use disorder. However, it has also been seen to significantly dampen the symptoms of depression and suicidal ideation, either in monotherapy or as an add-on therapy [26]. Furthermore, recent clinical trials have shown that ALKS-5461, a combination of buprenorphine and samidorphan (a MOR antagonist), can significantly alleviate depressive symptoms, with no signs of tolerance during the treatment or withdrawal symptoms following discontinuation [27]. However, such therapy has failed to be approved by the FDA as an adjunctive treatment for MDD as additional clinical data is still required to confirm its efficacy.
Morphine reduces mouse microglial engulfment induced by lipopolysaccharide and interferon-γ via δ opioid receptor and p38 mitogen-activated protein kinase
Published in Neurological Research, 2018
Jung-Hee Ryu, Sang-Hwan Do, Sung-Hee Han, Zhiyi Zuo
In conclusion, this in vitro experiment with C8-B4 microglial cells showed that morphine post-treatment at clinical relevant concentrations decreased microglial engulfment after activation by LPS plus IFN-γ. Delta (δ) opioid receptor seems to mediate this effect and p38 MAPK may also contribute to the mechanisms of this morphine effects. These results suggest the effect of morphine on microglial phagocytosis during neuroinflammation. However, microglial phagocytosis has both advantageous and injurious consequences during neuroinflammation. The consequence of morphine effect on microglial engulfment, especially under in vivo conditions, remains largely unknown.