N-Acylethanolamine Acid Amidase Inhibition Potentiates Morphine Analgesia and Delays the Development of Tolerance

AbstractOpioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates morphine’s antinociceptive effects and attenuates the development of morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3–30 mg/kg) enhanced the antinociceptive effects of morphine and delayed the development of tolerance to chronic morphine in behaving rats. Consistently, AM11095 enhanced morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic morphine were paralleled by a decrease in glial activation in the spinal cord, an index of opioid-induced neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the analgesic effects of opioids and delay the development of tolerance.

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The Role of Hydrogen Sulfide in the Development of Tolerance and Dependence to Morphine in Mice

Neuropsychobiology ◽

10.1159/000511541 ◽

2020 ◽

pp. 1-7

Author(s):

Zeynep Cetin ◽

Ozgur Gunduz ◽

Ruhan D. Topuz ◽

Dikmen Dokmeci ◽

Hakan C. Karadag ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Physical Dependence ◽

Morphine Tolerance ◽

Morphine Dependence ◽

Tail Flick ◽

Pain Mechanisms ◽

Antinociceptive Effects ◽

Synthase Inhibitor ◽

Development Of Tolerance

Objective: Hydrogen sulfide is an endogenous gaseous mediator that has been indicated to have a role in pain mechanisms. In this study, we aimed to detect brain and spinal cord hydrogen sulfide levels during different phases of tolerance and dependence to morphine and to determine the effects of inhibition of endogenous hydrogen sulfide production on the development of tolerance and dependence. Methods: Morphine tolerance and dependence was developed by subcutaneous injection of morphine (10 mg/kg) twice daily for 12 days. Physical dependence was determined by counting the jumps for 20 min, which is a withdrawal symptom occurring after a single dose of naloxone (5 mg/kg) administered intraperitoneally (i.p.). Propargylglycine (30 mg/kg, i.p.), a cystathionine-γ-lyase inhibitor, and hydroxylamine (12.5 mg/kg, i.p.), a cystathionine-β-synthase inhibitor, were used as hydrogen sulfide synthase inhibitors. The tail-flick and hot-plate tests were used to determine the loss of antinociceptive effects of morphine and development of tolerance. Results: It was found that chronic and acute uses of both propargylglycine and hydroxylamine prevented the development of tolerance to morphine, whereas they had no effect on morphine dependence. Chronic and acute administrations of hydrogen sulfide synthase inhibitors did not exert any difference in hydrogen sulfide levels in brain and spinal cords of both morphine-tolerant and -dependent animals. Conclusion: It has been concluded that hydrogen sulfide synthase inhibitors may have utility in preventing morphine tolerance.

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In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans

Journal of Neurophysiology ◽

10.1152/jn.00801.2011 ◽

2012 ◽

Vol 107 (1) ◽

pp. 357-363 ◽

Cited By ~ 32

Author(s):

C. Ma ◽

H. Nie ◽

Q. Gu ◽

P. Sikand ◽

R. H. LaMotte

Keyword(s):

Time Course ◽

Discharge Rate ◽

Receptive Fields ◽

Mechanical Stimuli ◽

Nociceptive Neurons ◽

Electrophysiological Recordings ◽

The Mean ◽

Chemical Stimuli ◽

Temporal Profiles

Native cowhage spicules, and heat-inactivated spicules containing histamine or capsaicin, evoke similar sensations of itch and nociceptive sensations in humans. In ongoing studies of the peripheral neural mechanisms of chemical itch and pain in the mouse, extracellular electrophysiological recordings were obtained, in vivo, from the cell bodies of mechanosensitive nociceptive neurons in response to spicule stimuli delivered to their cutaneous receptive fields (RFs) on the distal hindlimb. A total of 43 mechanosensitive, cutaneous, nociceptive neurons with axonal conduction velocities in the C-fiber range (C-nociceptors) were classified as CM if responsive to noxious mechanical stimuli, such as pinch, or CMH if responsive to noxious mechanical and heat stimuli (51°C, 5 s). The tips of native cowhage spicules, or heat-inactivated spicules containing histamine or capsaicin, were applied to the RF. Heat-inactivated spicules containing no chemical produced only a transient response occurring during insertion. Of the 43 mechanosensitive nociceptors recorded, 20 of the 25 CMHs responded to capsaicin, and of these, 13 also responded to cowhage and/or histamine. In contrast, none of the 18 CMs responded to any of the chemical stimuli. The time course of the mean discharge rate of CMHs was similar in response to each type of spicule and generally similar, although reaching a peak earlier, to the temporal profiles of itch and nociceptive sensations evoked by the same stimuli in humans. These findings are consistent with the hypothesis that the itch and nociceptive sensations evoked by these punctuate chemical stimuli are mediated at least in part by the activity of mechanoheat-sensitive C-nociceptors. In contrast, activity in mechanosensitive C-nociceptors that do not respond to heat or to pruritic chemicals is hypothesized as contributing to pain but not to itch.

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Evaluation of antinociceptive activity of Ilex dipyrena Wall. in mice

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03357-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Amjad Ali ◽

Abdul Nasir ◽

Syed Wadood Ali Shah ◽

Atif Ali Khan Khalil ◽

Mi-jeong Ahn ◽

...

Keyword(s):

Body Weight ◽

Acetic Acid ◽

Crude Extract ◽

Hot Plate ◽

Hot Plate Test ◽

Analgesic Effects ◽

Test Models ◽

Antinociceptive Effects ◽

Tail Immersion

Abstract Background In order to find a new natural resource for pain-relief, the analgesic effects of Ilex dipyrena crude extract, fractions, and subfractions were evaluated in in-vivo mouse models with possible mechanism of action. Methods Analgesic effects of crude extract (100 and 200 mg/kg body weight), fractions and subfractions (75 mg/kg body weight) were screened using heat-induced (tail-immersion and hot plate test) and chemical-induced (formalin and acetic acid) nociception models in mice. The samples were also tested for the elucidation of a possible mechanism through opioidergic and GABAergic systems. Results The administration of crude extract, fractions and subfractions produced analgesic responses in acetic acid, formalin, tail immersion, and hot plate model for pain similar to those obtained with the standard. Naloxone antagonized the antinociceptive effects of the tested samples, whereas bicuculline showed partial inhibition. Considering the analgesic response, crude extract, fractions, and subfractions demonstrated promising inhibitory activity against all test models for pain, which was further supported by the possible involvement of opioidergic and GABAergic systems. Conclusion The results suggest that this plant may be useful in the development of new analgesic drugs. Further research with regard to the isolation of bioactive compounds is required to verify these findings.

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Delay of Morphine Tolerance by Palmitoylethanolamide

BioMed Research International ◽

10.1155/2015/894732 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Lorenzo Di Cesare Mannelli ◽

Francesca Corti ◽

Laura Micheli ◽

Matteo Zanardelli ◽

Carla Ghelardini

Keyword(s):

Molecular Mechanisms ◽

Antinociceptive Effect ◽

Immunohistochemical Analysis ◽

Morphine Tolerance ◽

Cell Number ◽

Morphine Group ◽

Proinflammatory Mediators ◽

Antinociceptive Effects ◽

Endogenous Compound ◽

Development Of Tolerance

In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon.N-Palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg−1PEA was subcutaneously daily administered in morphine treated rats (10 mg kg−1intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-αlevels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-αimmunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested.

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Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol

Biomolecules ◽

10.3390/biom11040493 ◽

2021 ◽

Vol 11 (4) ◽

pp. 493

Author(s):

Lukas Barsch ◽

Robert Werdehausen ◽

Andreas Leffler ◽

Volker Eulenburg

Keyword(s):

Opioid Analgesic ◽

Allosteric Modulator ◽

Xenopus Laevis Oocytes ◽

Receptor Function ◽

Positive Allosteric Modulator ◽

Analgesic Effects ◽

Glycine Transporter ◽

Electrode Voltage ◽

Glycinergic Neurotransmission

Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a N,N-diethylester of acetaminophen, a non-opioid analgesic used to treat mild pain conditions. In vivo, it is hydrolysed into N,N-diethylglycine (DEG) and acetaminophen. DEG has structural similarities to known alternative GlyT1 substrates. In this study, we analyzed possible effects of propacetamol, or its metabolite N,N-diethylglycine (DEG), on GlyRs or GlyTs function by using a two-electrode voltage clamp approach in Xenopus laevis oocytes. Our data demonstrate that, although propacetamol or acetaminophen had no effect on the function of the analysed glycine-responsive proteins, the propacetamol metabolite DEG acted as a low-affine substrate for both GlyT1 (EC50 > 7.6 mM) and GlyT2 (EC50 > 5.2 mM). It also acted as a mild positive allosteric modulator of GlyRα1 function at intermediate concentrations. Taken together, our data show that DEG influences both glycine transporter and receptor function, and therefore could facilitate glycinergic neurotransmission in a multimodal manner.

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Low-dose Lidocaine Suppresses Experimentally Induced Hyperalgesia in Humans

Anesthesiology ◽

10.1097/00000542-199812000-00011 ◽

1998 ◽

Vol 89 (6) ◽

pp. 1345-1353 ◽

Cited By ~ 66

Author(s):

Wolfgang Koppert ◽

Susanne Zeck ◽

Reinhard Sittl ◽

Rudolf Likar ◽

Rainer Knoll ◽

...

Keyword(s):

Regional Anesthesia ◽

Local Anesthetics ◽

Low Dose ◽

Experimental Pain ◽

Mechanical Stimuli ◽

Axon Reflex ◽

Analgesic Effects ◽

Intravenous Regional Anesthesia ◽

Low Concentrations ◽

Antinociceptive Effects

Background The antinociceptive effects of systemically administered local anesthetics have been shown in various conditions, such as neuralgia, polyneuropathy, fibromyalgia, and postoperative pain. The objective of the study was to identify the peripheral mechanisms of action of low-dose local anesthetics in a model of experimental pain. Methods In a first experimental trial, participants (n=12) received lidocaine systemically (a bolus injection of 2 mg/kg in 10 min followed by an intravenous infusion of 2 mg x kg(-1) x h(-1) for another 50 min). In a second trial, modified intravenous regional anesthesia was administered to exclude possible central analgesic effects. In one arm, patients received an infusion of 40 ml lidocaine, 0.05%; in their other arm, 40 ml NaCl, 0.9%, served as a control. In both trials, calibrated tonic and phasic mechanical and chemical (histamine) stimuli were applied to determine differentially the impairment of tactile and nociceptive perception. Results Mechanical sensitivity to touch, phasic mechanical stimuli of noxious intensity, and heat pain thresholds remained unchanged after systemic and regional application of the anesthetic. In contrast, histamine-induced itch (intravenous regional anesthesia), axon reflex flare (systemic treatment), and development of acute mechanical hyperalgesia during tonic pressure (12 N; 2 min) of an interdigital web was significantly suppressed after both treatments. Conclusions Increasing painfulness during sustained pinching has been attributed to excitation and simultaneous sensitization of particular Adelta- and C-nociceptors. This hyperalgesic mechanism seems to be particularly sensitive to low concentrations of lidocaine. These findings confirm clinical experience with lidocaine in pain states dominated by hyperalgesia.

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In vivo CNS Depressant and Antinociceptive Studies of Microcos paniculata Stem Extracts on Animal Model

Bangladesh Pharmaceutical Journal ◽

10.3329/bpj.v20i1.32092 ◽

2017 ◽

Vol 20 (1) ◽

pp. 39-45

Author(s):

Md Anamul Haque ◽

Md Anwarul Haque ◽

Md Anwar Ul Islam

Keyword(s):

Central Nervous System ◽

Open Field ◽

Analgesic Effect ◽

Pharmaceutical Journal ◽

Depressant Effect ◽

Hot Plate ◽

Analgesic Effects ◽

Cns Depressant ◽

Antinociceptive Effects

The main objective of the study was to evaluate the possible central nervous system (CNS) depressant and antinociceptive effects of methanol (MMPS), petroleum ether (PMPS), chloroform (CMPS), dichloromethane (DMPS) and aqueous (AMPS) extracts of the Microcos paniculata (M. paniculata). The CNS-depressant effect of different extracts of M. paniculata stem on Swiss albino mice was assessed by using open field, hole cross and head deep tests at 100 and 200 mg/kg dose. Analgesic effect was evaluated by acetic acid-induced writhing and hot plate methods at 100 and 200 mg/kg dose. All the extracts had exhibited significant (Pb < 0.01, Pa < 0.001) CNS depressant and analgesic effects in a dose dependant manner. MMPS had shown highest CNSdepressant effect with 93.39% inhibition of mice movement (open field), 78.92% inhibition of hole cross and 86.90% inhibition of head deeping at 200 mg/kg dose. Besides, DMPS extracts showed maximum analgesic effect with 75.52% inhibition of abdominal writhing and 65.55% elongation of paw licking time at 200mg/kg dose. Among the five extracts, MMPS possesses potent CNS depressant effect while DMPS possesses potent analgesic effect. These findings may expose effectiveness of the extracts on anxiety and pain that may help to formulate a herbal medicine or to search a lead compound.Bangladesh Pharmaceutical Journal 20(1): 39-45, 2017

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Rapid tolerance to morphine in the myenteric neurons of the small intestine is independent of β-arrestin-2 and mediated by PKC

10.1101/2020.07.17.209437 ◽

2020 ◽

Cited By ~ 1

Author(s):

Karan H. Muchhala ◽

Joanna C. Jacob ◽

Imran Alam ◽

Shahzeb Hasan ◽

Aliyeen Khan ◽

...

Keyword(s):

Small Intestine ◽

G Protein ◽

Morphine Tolerance ◽

List Type ◽

Chronic Morphine ◽

Opioid Agonist ◽

Tolerance Development ◽

Myenteric Neurons ◽

Opioid Agonists

AbstractBackground and PurposeG-protein biased μ-opioid agonists against β-arrestin-2 activation are being investigated to reduce adverse effects. While opioid tolerance is strongly linked to the development of dependence, there is a dissociation between the two phenomena in the gut as tolerance does not develop to opioid-induced constipation, but diarrhea still manifests upon withdrawal. Here, we investigated the mechanism by which morphine tolerance in the small intestine develops.Experimental ApproachMechanism of morphine tolerance in the small intestine was evaluated in vivo and at the neuronal level. Whole-cell patch clamp electrophysiology was used to investigate tolerance in individual ileum myenteric neurons. Rate of morphine tolerance development in the small intestine was assessed against peripheral antinociception and whole gut transit.Key ResultsTolerance develops to inhibition of small intestinal motility after one day of morphine exposure, and is more rapid compared to peripheral antinociception and constipation in chronic morphine-treated mice. Morphine tolerance was reversed by the PKC inhibitor, Tamoxifen, but not by β-arrestin-2 deletion. Similarly, β-arrestin-2 deletion did not prevent morphine tolerance to inhibition of neuronal excitability in ileum myenteric neurons. However, neuronal tolerance was attenuated by inhibiting PKC.Conclusions and ImplicationsUnlike antinociceptive tolerance, rapid morphine tolerance in the small intestine is independent of β-arrestin-2 but is PKC-mediated. These findings reveal a potential mechanism for differences in the rates of tolerances to opioids, implicate myenteric neurons of the ileum as the primary cause for opioid-induced withdrawal effects and suggest that undesired gastrointestinal effects will persist with biased opioid agonist use.SummaryWhat is already known:Tolerance does not develop to chronic-opioid-induced constipation but diarrhea is produced upon withdrawalNovel G-protein biased agonists that preclude β-arrestin-2 activation at the μ-opioid receptor are in developmentWhat this study adds:Morphine tolerance in the ileum develops systemically and in individual myenteric neurons independent of β-arrestin-2Morphine tolerance in the small intestine develops before antinociception and is reversed by PKC inhibitionClinical significance:Clinical use of G-protein biased opioid agonists will not prevent tolerance development in the ileumTolerance in ileum myenteric neurons might be the basis of opioid-induced withdrawal in the gut

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