Chemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression

Inan, Saadet; Chen, Xiaohong; Eisenstein, Eric M.; Meissler, Joseph J.; Geller, Ellen B.; Tallarida, Christopher S.; Watson, Mia N.; Doura, Menahem B.; Barrett, James E.; Cowan, Alan; Adler, Martin W.; Eisenstein, Toby K.

doi:10.1016/j.lfs.2021.120014

Cited by 6 publications

(5 citation statements)

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“…Considering the fact that monotherapy has low effectiveness against neuropathy [ 65 ], we decided to check whether the new selective pharmacological tools can increase the effectiveness of morphine after combined administration. It is well known that apart from increasing therapeutic effectiveness, drug coadministration also reduces the risk of side effects because of the possibility of lower dose usage [ 66 ]. In our opinion, combined pharmacotherapy based on two analgesics is reasonable if the drugs used have different mechanisms of action, as in the case of modulators of opioid and chemokine system coadministration.…”

Section: Discussionmentioning

confidence: 99%

“…Given that opioid receptors can probably form heterodimers with CCR1 and CCR5, the combined administration of opioid agonists with chemokine antagonists appears to be a new, interesting strategy for the relief of chronic pain. This is particularly important because it has been shown that such drug combinations allow for the use of lower doses of opioids and consequently result in less respiratory depression [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

et al. 2023

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Neuropathic pain pathophysiology is not fully understood, but it was recently shown that MIP-1 family members (CCL3, CCL4, and CCL9) have strong pronociceptive properties. Our goal was to examine how pharmacological modulation of these chemokines and their receptors (CCR1 and CCR5) influence hypersensitivity after nerve injury in Albino Swiss male mice. The spinal changes in the mRNA/protein levels of the abovementioned chemokines and their receptors were measured using RT-qPCR and ELISA/Western blot techniques in a mouse model of chronic constriction injury of the sciatic nerve. Behavioral studies were performed using the von Frey and cold plate tests after pharmacological treatment with neutralizing antibodies (nAbs) against chemokines or antagonists (CCR1-J113863, CCR5-TAK-220/AZD-5672) alone and in coadministration with morphine on Day 7, when the hypersensitivity was fully developed. Our results showed enhanced protein levels of CCL3 and CCL9 1 and 7 days after nerve injury. The single intrathecal administration of CCL3 or CCL9 nAb, J113863, TAK-220, or AZD-5672 diminished neuropathic pain symptoms and enhanced morphine analgesia. These findings highlight the important roles of CCL3 and CCL9 in neuropathic pain and additionally indicate that these chemokines play essential roles in opioid analgesia. The obtained results suggest CCR1 and CCR5 as new, interesting targets in neuropathy treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

et al. 2023

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“…Pulse oximeters (STARR Life Sciences® Corp) were used to monitor the oxygen saturation of experimental mice in real‐time while awake 17 . The day before the experiment, we shaved the necks of all mice because dark hairs interfere with detecting light signals.…”

Section: Methodsmentioning

confidence: 99%

“…Pulse oximeters (STARR Life Sciences® Corp) were used to monitor the oxygen saturation of experimental mice in real‐time while awake. 17 The day before the experiment, we shaved the necks of all mice because dark hairs interfere with detecting light signals. At the same time, we clamped the test clips on the necks of the mice and placed them in the experimental cage to adapt to the environment.…”

Section: Methodsmentioning

confidence: 99%

APP^swe/PS1^ΔE9 mice exhibit low oxygen saturation and alterations of erythrocytes preceding the neuropathology and cognitive deficiency during Alzheimer's disease

et al. 2023

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Aim The molecular mechanism underlying Alzheimer's disease (AD) pathologies remains unclear. The brain is extremely sensitive to oxygen deprivation, and brief interruptions in oxygen supply may lead to permanent brain damage. The objective here was to access the red blood cell (RBC) physiological alterations and the changes in blood oxygen saturation of an AD model as well as to explore the possible mechanism underlying these pathologies. Methods We used female APPswe/PS1ΔE9 mice as AD models. Data were collected at the age of 3, 6, and 9 months. In addition to examining classic features of AD, namely cognitive deficiency and Aβ depositions, 24 h blood oxygen saturation was monitored by Plus oximeters in real time. In addition, RBC physiological parameters were measured by blood cell counter using peripheral blood from the epicanthal veins. Furthermore, in the mechanism investigations, the expression of phosphorylated band 3 protein was examined by a series of Western blot analyses, and the levels of soluble Aβ40 and Aβ42 on the membrane of RBCs were determined by ELISA. Results Our results showed that the blood oxygen saturation in the AD mice was significantly reduced as early as at 3 months of age, preceding the neuropathological changes and cognitive impairments. Meanwhile, the expression of phosphorylated band 3 protein and levels of soluble Aβ40 and Aβ42 were all elevated in the erythrocytes of the AD mice. Conclusion APPswe/PS1ΔE9 mice exhibited decreased oxygen saturation together with reduced RBC counts and hemoglobin concentrations at the early stage, which may aid in the development of predictive markers for AD diagnosis. The increased expression of band 3 protein and elevated Aβ40 and Aβ42 levels may contribute to the deformation of RBCs and, in turn, cause the subsequent AD development.

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“…Experiments were performed as described by Inan et al (2021). On the day of the experiment, mice were brought to the room and acclimated for 45-60 min in the observation boxes.…”

Section: Measurement Of Respiration In Micementioning

confidence: 99%

NCP, a Dual Kappa and Mu Opioid Receptor Agonist, Is a Potent Analgesic Against Inflammatory Pain without Reinforcing or Aversive Properties

Huang,

Ho,

Cao

et al. 2024

J Pharmacol Exp Ther

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While agonists of  (MOR) and (KOR) opioid receptors have analgesic effects, they produce euphoria and dysphoria, respectively. Other side effects include respiratory depression and addiction for MOR agonists and sedation for KOR agonists. We reported that 17-cyclopropylmethyl-3,14β-dihydroxy-4,5αepoxy-6β-{[4′-(2′-cyanopyridyl)]carboxamido}cmorphinan (NCP) displayed potent KOR full agonist and MOR partial agonist activities (58%) with 6.5x KOR-over-MOR selectivity in vitro. Herein, we characterized pharmacological effects of NCP in rodents. In mice, NCP exerted analgesic effects against inflammatory pain in both the formalin test and the acetic acid writhing test, with A 50 values of 47.6 and 14.4 g/kg (s.c.), respectively. The analgesic effects in the acetic acid writhing test were mediated by the KOR. NCP at doses much higher than those effective in reducing inflammatory pain did not produce antinociception in the hot plate and tail flick tests, inhibit compound 48/80-induced scratching, cause conditioned place aversion (CPA) or preference, impair rotarod performance, inhibit locomotor activity, cause respiratory depression, or precipitate morphine withdrawal. However, NCP (10~100 g/kg) inhibited gastrointestinal transit with a maximum of ~40% inhibition. In MOR knockout mice, NCP caused CPA, demonstrating that its lack of CPA is due to combined actions on the MOR and KOR. Following s.c. injection, NCP penetrated into the mouse brain. In rats trained to selfadminister heroin, NCP (1~320 g/kg/infusion) did not function as a reinforcer. Thus, NCP produces potent analgesic effects via KOR without side effects except constipation. Therefore, dual full KOR/partial MOR agonists with moderate KOR-over-MOR selectivity may be promising as nonaddictive analgesics for inflammatory pain.

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Chemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression

Cited by 6 publications

References 53 publications

Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

APP^swe/PS1^ΔE9 mice exhibit low oxygen saturation and alterations of erythrocytes preceding the neuropathology and cognitive deficiency during Alzheimer's disease

NCP, a Dual Kappa and Mu Opioid Receptor Agonist, Is a Potent Analgesic Against Inflammatory Pain without Reinforcing or Aversive Properties

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Chemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression

Cited by 6 publications

References 53 publications

Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

APPswe/PS1ΔE9 mice exhibit low oxygen saturation and alterations of erythrocytes preceding the neuropathology and cognitive deficiency during Alzheimer's disease

NCP, a Dual Kappa and Mu Opioid Receptor Agonist, Is a Potent Analgesic Against Inflammatory Pain without Reinforcing or Aversive Properties

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APP^swe/PS1^ΔE9 mice exhibit low oxygen saturation and alterations of erythrocytes preceding the neuropathology and cognitive deficiency during Alzheimer's disease