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1.
Mol Pain ; 16: 1744806920950866, 2020.
Article in English | MEDLINE | ID: mdl-32811276

ABSTRACT

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of experimental neuropathy, protect and stimulate regeneration of sensory neurons in animal models of neuropathic pain, and restore their functional activity. However, clinical development of GFL proteins is complicated by their poor pharmacokinetic properties and multiple effects mediated by several receptors. Previously, we have identified a small molecule that selectively activates the major signal transduction unit of the GFL receptor complex, receptor tyrosine kinase RET, as an alternative to GFLs, for the treatment of neuropathic pain. We then introduced a series of chemical changes to improve the biological activity of these compounds and tested an optimized compound named BT44 in a panel of biological assays. BT44 efficiently and selectively stimulated the GFL receptor RET and activated the intracellular mitogene-activated protein kinase/extracellular signal-regulated kinase pathway in immortalized cells. In cultured sensory neurons, BT44 stimulated neurite outgrowth with an efficacy comparable to that of GFLs. BT44 alleviated mechanical hypersensitivity in surgery- and diabetes-induced rat models of neuropathic pain. In addition, BT44 normalized, to a certain degree, the expression of nociception-related neuronal markers which were altered by spinal nerve ligation, the neuropathy model used in this study. Our results suggest that the GFL mimetic BT44 is a promising new lead for the development of novel disease-modifying agents for the treatment of neuropathy and neuropathic pain.


Subject(s)
Biomimetics/methods , Neuralgia/drug therapy , Proto-Oncogene Proteins c-ret/agonists , Proto-Oncogene Proteins c-ret/metabolism , Sensory Receptor Cells/drug effects , Signal Transduction/drug effects , Spinal Nerves/drug effects , Animals , Behavior Rating Scale , Cell Line , Diabetic Neuropathies/drug therapy , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism , Glial Cell Line-Derived Neurotrophic Factors , Immunohistochemistry , Male , Nerve Tissue Proteins/metabolism , Neuralgia/metabolism , Nociception/drug effects , Phosphorylation , Rats , Rats, Wistar , Sensory Receptor Cells/metabolism , Spinal Nerves/injuries
2.
Eur J Pharmacol ; 875: 173021, 2020 May 15.
Article in English | MEDLINE | ID: mdl-32112778

ABSTRACT

Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.


Subject(s)
Central Nervous System Stimulants/pharmacology , Hyperalgesia/chemically induced , Morphine Derivatives/pharmacology , Morphine/pharmacology , Nociception/drug effects , Animals , Disease Models, Animal , Drug Administration Schedule , Drug Tolerance , Humans , Hyperalgesia/diagnosis , Injections, Spinal , Male , Morphine/metabolism , Morphine Derivatives/metabolism , Pain Measurement , Rats , Spinal Cord/drug effects , Spinal Cord/metabolism , Substance P/metabolism
3.
Neuroscience ; 375: 10-24, 2018 04 01.
Article in English | MEDLINE | ID: mdl-29421434

ABSTRACT

Development of tolerance is a well known pharmacological characteristic of opioids and a major clinical problem. In addition to the known neuronal mechanisms of opioid tolerance, activation of glia has emerged as a potentially significant new mechanism. We studied activation of microglia and astrocytes in morphine tolerance and opioid-induced hyperalgesia in rats using immunohistochemistry, flow cytometry and RNA sequencing in spinal- and supraspinal regions. Chronic morphine treatment that induced tolerance and hyperalgesia also increased immunoreactivity of spinal microglia in the dorsal and ventral horns. Flow cytometry demonstrated that morphine treatment increased the proportion of M2-polarized spinal microglia, but failed to impact the number or the proportion of M1-polarized microglia. In the transcriptome of microglial cells isolated from the spinal cord (SC), morphine treatment increased transcripts related to cell activation and defense response. In the studied brain regions, no activation of microglia or astrocytes was detected by immunohistochemistry, except for a decrease in the number of microglial cells in the substantia nigra. In flow cytometry, morphine caused a decrease in the number of microglial cells in the medulla, but otherwise no change was detected for the count or the proportion of M1- and M2-polarized microglia in the medulla or sensory cortex. No evidence for the activation of glia in the brain was seen. Our results suggest that glial activation associated with opioid tolerance and opioid-induced hyperalgesia occurs mainly at the spinal level. The transcriptome data suggest that the microglial activation pattern after chronic morphine treatment has similarities with that of neuropathic pain.


Subject(s)
Analgesics, Opioid/pharmacology , Brain/drug effects , Morphine/pharmacology , Neuroglia/drug effects , Spinal Cord/drug effects , Animals , Brain/metabolism , Brain/pathology , Drug Tolerance , Hyperalgesia/metabolism , Hyperalgesia/pathology , Male , Models, Animal , Neuroglia/metabolism , Neuroglia/pathology , Nociceptive Pain/drug therapy , Nociceptive Pain/metabolism , Nociceptive Pain/pathology , Rats, Sprague-Dawley , Spinal Cord/metabolism , Spinal Cord/pathology , Transcriptome/drug effects
4.
Basic Clin Pharmacol Toxicol ; 122(5): 481-488, 2018 May.
Article in English | MEDLINE | ID: mdl-29171155

ABSTRACT

Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-d-aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of α7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6-hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high-performance liquid chromatography-tandem mass spectrometry. Ketamine (10 mg/kg), but not 6-hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6-hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6-hydroxynorketamine were doubled by morphine pre-treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co-administration of 6-hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6-hydroxynorketamine brain concentrations were increased after co-administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6-hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.


Subject(s)
Analgesics, Opioid/pharmacology , Anesthetics, Dissociative/pharmacology , Behavior, Animal/drug effects , Brain/drug effects , Drug Tolerance , Ketamine/analogs & derivatives , Morphine/pharmacology , Nociceptive Pain/prevention & control , Analgesics, Opioid/blood , Analgesics, Opioid/pharmacokinetics , Anesthetics, Dissociative/blood , Anesthetics, Dissociative/pharmacokinetics , Animals , Brain/metabolism , Brain/physiopathology , Disease Models, Animal , Drug Interactions , Ketamine/blood , Ketamine/pharmacokinetics , Ketamine/pharmacology , Male , Morphine/blood , Morphine/pharmacokinetics , Motor Activity/drug effects , Nociception/drug effects , Nociceptive Pain/blood , Nociceptive Pain/physiopathology , Nociceptive Pain/psychology , Pain Threshold/drug effects , Rats, Sprague-Dawley
5.
Front Pharmacol ; 8: 365, 2017.
Article in English | MEDLINE | ID: mdl-28680400

ABSTRACT

Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage. Two candidate targets are glial cell line-derived neurotrophic factor (GDNF) and artemin (ARTN), as these GDNF family ligands (GFLs) show efficacy in animal models of neuropathic pain (Boucher et al., 2000; Gardell et al., 2003; Wang et al., 2008, 2014). As these protein ligands have poor drug-like properties and are expensive to produce for clinical use, we screened 18,400 drug-like compounds to develop small molecules that act similarly to GFLs (GDNF mimetics). This screening identified BT13 as a compound that selectively targeted GFL receptor RET to activate downstream signaling cascades. BT13 was similar to NGF and ARTN in selectively promoting neurite outgrowth from the peptidergic class of adult sensory neurons in culture, but was opposite to ARTN in causing neurite elongation without affecting initiation. When administered after spinal nerve ligation in a rat model of neuropathic pain, 20 and 25 mg/kg of BT13 decreased mechanical hypersensitivity and normalized expression of sensory neuron markers in dorsal root ganglia. In control rats, BT13 had no effect on baseline mechanical or thermal sensitivity, motor coordination, or weight gain. Thus, small molecule BT13 selectively activates RET and offers opportunities for developing novel disease-modifying medications to treat neuropathic pain.

6.
Basic Clin Pharmacol Toxicol ; 120(1): 38-45, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27312359

ABSTRACT

Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co-administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)- and morphine (3 mg/kg, s.c.)-induced antinociception using tail-flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system.


Subject(s)
Analgesics/therapeutic use , Brain/drug effects , Disease Models, Animal , Diuretics/therapeutic use , Neurons/drug effects , Pain/prevention & control , Spironolactone/therapeutic use , Analgesics, Opioid/blood , Analgesics, Opioid/metabolism , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/therapeutic use , Animals , Behavior, Animal/drug effects , Brain/metabolism , Chlorothiazide/therapeutic use , Drug Interactions , Drug Therapy, Combination , Eplerenone , Furosemide/therapeutic use , Male , Morphine/blood , Morphine/metabolism , Morphine/pharmacokinetics , Morphine/therapeutic use , Neurons/metabolism , Oxycodone/blood , Oxycodone/metabolism , Oxycodone/pharmacokinetics , Oxycodone/therapeutic use , Pain/blood , Pain/metabolism , Rats, Sprague-Dawley , Spironolactone/analogs & derivatives , Tissue Distribution
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