<i>In vivo</i> effects of μ‐opioid receptor agonist/δ‐opioid receptor antagonist peptidomimetics following acute and repeated administration

Anand, Jessica P.; Kochan, Kelsey; Nastase, Anthony; Montgomery, Dan; Griggs, Nicholas W.; Traynor, John R.; Mosberg, Henry I.; Jutkiewicz, Emily M.

doi:10.1111/bph.14148

Cited by 32 publications

(80 citation statements)

References 49 publications

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“…To induce opioid analgesic tolerance, morphine was injected I.P. at 10 mg/kg, twice per day, for 8 consecutive days, as described previously (Anand et al 2018).…”

Section: Drug Administrationmentioning

confidence: 99%

μ‐Opioid receptors in primary sensory neurons are essential for opioid analgesic effect on acute and inflammatory pain and opioid‐induced hyperalgesia

Sun

Chen

et al. 2019

The Journal of Physiology

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Key points μ‐Opioid receptors (MORs) are expressed peripherally and centrally, but the loci of MORs responsible for clinically relevant opioid analgesia are uncertain. Crossing Oprm1flox/flox and AdvillinCre/+ mice completely ablates MORs in dorsal root ganglion neurons and reduces the MOR expression level in the spinal cord. Presynaptic MORs expressed at primary afferent central terminals are essential for synaptic inhibition and potentiation of sensory input by opioids. MOR ablation in primary sensory neurons diminishes analgesic effects produced by systemic and intrathecal opioid agonists and abolishes chronic opioid treatment‐induced hyperalgesia. These findings demonstrate a critical role of MORs expressed in primary sensory neurons in opioid analgesia and suggest new strategies to increase the efficacy and reduce adverse effects of opioids. Abstract The pain and analgesic systems are complex, and the actions of systemically administered opioids may be mediated by simultaneous activation of μ‐opioid receptors (MORs, encoded by the Oprm1 gene) at multiple, interacting sites. The loci of MORs and circuits responsible for systemic opioid‐induced analgesia and hyperalgesia remain unclear. Previous studies using mice in which MORs are removed from Nav1.8‐ or TRPV1‐expressing neurons provided only an incomplete and erroneous view about the role of peripheral MORs in opioid actions in vivo. In the present study, we determined the specific role of MORs expressed in primary sensory neurons in the analgesic and hyperalgesic effects produced by systemic opioid administration. We generated Oprm1 conditional knockout (Oprm1‐cKO) mice in which MOR expression is completely deleted from dorsal root ganglion neurons and substantially reduced in the spinal cord, which was confirmed by immunoblotting and immunocytochemical labelling. Both opioid‐induced inhibition and potentiation of primary sensory input were abrogated in Oprm1‐cKO mice. Remarkably, systemically administered morphine potently inhibited acute thermal and mechanical nociception and persistent inflammatory pain in control mice but had little effect in Oprm1‐cKO mice. The analgesic effect of intrathecally administered morphine was also profoundly reduced in Oprm1‐cKO mice. Additionally, chronic morphine treatment‐induced hyperalgesia was absent in Oprm1‐cKO mice. Our findings directly challenge the notion that clinically relevant opioid analgesia is mediated mostly by centrally expressed MORs. MORs in primary sensory neurons, particularly those expressed presynaptically at the first sensory synapse in the spinal cord, are crucial for both opioid analgesia and opioid‐induced hyperalgesia.

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“…To induce opioid analgesic tolerance, morphine was injected I.P. at 10 mg/kg, twice per day, for 8 consecutive days, as described previously (Anand et al 2018).…”

Section: Drug Administrationmentioning

confidence: 99%

μ‐Opioid receptors in primary sensory neurons are essential for opioid analgesic effect on acute and inflammatory pain and opioid‐induced hyperalgesia

Sun

Chen

et al. 2019

The Journal of Physiology

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“…Mixed action DOR/MOR agonists such as MMP-2200 reportedly do not produce CPP and exhibit limited reinforcing effects [ 29 ]. Isomer 5 also displayed DOR antagonism which has been shown to prevent the conditioned place preference of MOR agonists in studies of bivalent ligands [ 30 ] and peptidomimetics [ 31 ]. To the best of our knowledge, no one has examined the effect of combined KOR agonists/DOR agonists or antagonists.…”

Section: Discussionmentioning

confidence: 99%

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

et al. 2020

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The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.

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“…In the paper [109], the analgesic action and side effects of three peptidomimetics AAH8, AMB46, and AMB47, which are agonists of μ-opioid receptors and antagonists of δ-opioid receptors, were tested in animal models using the warm water tail withdrawal test. Morphine was used as the reference drug.…”

Section: Targets Of Analgesic and Antipruritic Therapymentioning

confidence: 99%

Psychotropic Drugs for the Management of Chronic Pain and Itch

Belinskaia

Barygin

et al. 2019

Pharmaceuticals

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Clinical observations have shown that patients with chronic neuropathic pain or itch exhibit symptoms of increased anxiety, depression and cognitive impairment. Such patients need corrective therapy with antidepressants, antipsychotics or anticonvulsants. It is known that some psychotropic drugs are also effective for the treatment of neuropathic pain and pruritus syndromes due to interaction with the secondary molecular targets. Our own clinical studies have identified antipruritic and/or analgesic efficacy of the following compounds: tianeptine (atypical tricyclic antidepressant), citalopram (selective serotonin reuptake inhibitor), mianserin (tetracyclic antidepressant), carbamazepine (anticonvulsant), trazodone (serotonin antagonist and reuptake inhibitor), and chlorprothixene (antipsychotic). Venlafaxine (serotonin-norepinephrine reuptake inhibitor) is known to have an analgesic effect too. The mechanism of such effect of these drugs is not fully understood. Herein we review and correlate the literature data on analgesic/antipruritic activity with pharmacological profile of these compounds.

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In vivo effects of μ‐opioid receptor agonist/δ‐opioid receptor antagonist peptidomimetics following acute and repeated administration

Abstract: AAH8 may be a better alternative than traditional opioid analgesics, producing antinociception with less development of tolerance and dependence and may be less rewarding than morphine.

Cited by 32 publications

References 49 publications

μ‐Opioid receptors in primary sensory neurons are essential for opioid analgesic effect on acute and inflammatory pain and opioid‐induced hyperalgesia

μ‐Opioid receptors in primary sensory neurons are essential for opioid analgesic effect on acute and inflammatory pain and opioid‐induced hyperalgesia

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

Psychotropic Drugs for the Management of Chronic Pain and Itch

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