Spinal and Peripheral Mechanisms Involved in the Enhancement of Morphine Analgesia in Acutely Inflamed Mice (original) (raw)
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European Journal of Pharmacology, 2009
The aim of this study is to investigate the involvement of nitric oxide synthesized by the inducible (NOS2) or neuronal (NOS1) nitric oxide synthases in the local antinociceptive effects produced by µ-and δ-opioid receptor agonists during chronic inflammatory pain. Peripheral inflammatory pain was induced in NOS2 and NOS1 knockout mice and their wild type littermates by the subplantar administration of complete Freund's adjuvant (30 µl). The presence of paw inflammation, mechanical allodynia and thermal hyperalgesia induced by complete Freund's adjuvant were assessed by measuring paw diameter and using the von Frey filaments and plantar tests, respectively. During chronic inflammation, NOS2 deficient mice have a more rapid recovery of paw edema and a reduced thermal hyperalgesia compared to wild type. In contrast, a reduced paw edema and mechanical allodynia, as well as a modest rapid recovery from thermal hyperalgesia were observed in NOS1 knockout mice compared to wild type. The thermal hyperalgesia induced by complete Freund's adjuvant was not completely reversed by the subplantar administration of morphine (days 4 and 7) or 5 ] enkephalin (DPDPE) (days 1 and 4) in NOS2 knockout mice as occurs in wild type mice. Moreover, the local administration of morphine or DPDPE also failed to reverse the decrease of ipsilateral paw withdrawal latency induced by complete Freund's adjuvant in NOS1 knockout mice throughout 10 days of peripheral inflammation. These results indicate the different roles played by nitric oxide synthesized by NOS2 or NOS1 in the maintenance of mechanical allodynia and thermal hyperalgesia induced by chronic inflammatory pain as well as, in the antinociceptive effects produced by µ-and δ-opioid receptor agonists during peripheral inflammatory pain.
Psychopharmacology, 2013
Rationale Treatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer, CORM-2) or a classical heme oxygenase 1 inducer (cobalt protoporphyrin IX, CoPP) has potent anti-inflammatory effects, but the role played by these treatments in the antinociceptive effects of morphine during acute and chronic pain was not evaluated. Objectives In wild type (WT), neuronal (NOS1-KO), or inducible (NOS2-KO) nitric oxide synthases knockout mice, we evaluated the effects of CORM-2 and CoPP treatments in the antinociceptive actions of morphine and their interaction with nitric oxide during acute, visceral, and chronic inflammatory or neuropathic pain. Methods Acute and visceral pain was assessed through formalin and acid acetic writhing tests. Chronic inflammatory pain induced by the intra-articular administration of complete Freund's adjuvant and neuropathic pain by partial ligation of sciatic nerve were evaluated by measuring allodynia and hyperalgesia using the von Frey filaments, plantar, or cold plate tests. Results While nitric oxide, synthetized by NOS1 and/or NOS2, increased the local antinociceptive effects of morphine during acute and chronic pain, it decreased the inhibitory effects of morphine after visceral pain. Moreover, while CORM-2 or CoPP treatments did not alter or reduced the antinociceptive effects of morphine during acute and visceral pain, both treatments improved the local antiallodynic and antihyperalgesic effects of morphine after chronic inflammatory or neuropathic pain in WT, but not in KO mice. Conclusions CORM-2 and CoPP treatments improved the local antinociceptive effects of morphine during chronic inflammatory and neuropathic pain by interaction with nitric oxide synthetized by NOS1 and NOS2 isoforms.
Proceedings of the National Academy of Sciences of the United States of America, 2010
Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3Kγ/AKT protein kinase B (AKT) and culminated in increased activation of K ATP channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development.
Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain
Journal of Clinical Investigation, 2008
Although opioids are highly effective analgesics, they are also known to induce cellular adaptations resulting in tolerance. Experimental studies are often performed in the absence of painful tissue injury, which precludes extrapolation to the clinical situation. Here we show that rats with chronic morphine treatment do not develop signs of tolerance at peripheral μ-opioid receptors (μ-receptors) in the presence of painful CFA-induced paw inflammation. In sensory neurons of these animals, internalization of μ-receptors was significantly increased and G protein coupling of μ-receptors as well as inhibition of cAMP accumulation were preserved. Opioid receptor trafficking and signaling were reduced, and tolerance was restored when endogenous opioid peptides in inflamed tissue were removed by antibodies or by depleting opioid-producing granulocytes, monocytes, and lymphocytes with cyclophosphamide (CTX). Our data indicate that the continuous availability of endogenous opioids in inflamed tissue increases recycling and preserves signaling of μ-receptors in sensory neurons, thereby counteracting the development of peripheral opioid tolerance. These findings infer that the use of peripherally acting opioids for the prolonged treatment of inflammatory pain associated with diseases such as chronic arthritis, inflammatory neuropathy, or cancer, is not necessarily accompanied by opioid tolerance.
Morphine peripheral analgesia depends on activation of the PI3K /AKT/nNOS/NO/KATP signaling pathway
Proceedings of The National Academy of Sciences, 2010
Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3Kγ/AKT protein kinase B (AKT) and culminated in increased activation of K ATP channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development.
The Journal of pharmacology and experimental therapeutics, 2016
Growing data support the peripheral opioid antinociceptive effect, particularly, in inflammatory pain models. Here, we examined the antinociceptive effects of the subcutaneously (s.c.) administered, recently synthesized 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) compared to morphine-6-O-sulfate (M6SU) in a rat model of inflammatory pain, induced by an injection of Complete Freund's Adjuvant (CFA) and a mouse model of visceral pain evoked by acetic acid. The s.c. doses of 14-O-MeM6SU and M6SU up to 126 and 547 nmol/kg, respectively produced significant and s.c. or intraplantar (i.pl.) naloxone methiodide (NAL-M) reversible antinociception in inflamed paws compared to non-inflamed paws. These certain doses neither of them affected significantly the thiobutabarbital's sleeping time or rat pulmonary parameters. However, the antinociceptive effects of higher doses were only partially reversed by NAL-M indicating CNS contribution. In mouse writhing test, 14-O-MeM6SU was more po...
Stimulation of peripheral nociceptor endings by low dose morphine and its signaling mechanism
Neurochemistry International, 2002
In this report, we demonstrated that peripheral application of very low dose (amol ranges) of morphine induced flexor response through a substance P (SP) release at the nociceptor endings in mice. The intraplantar (i.pl.) application of morphine produced flexor response in a dose-dependent manner from 0.1 to 1000 amol. The-opioid receptor (MOP-R) agonist [d-Ala 2 ,N-Me-Phe 4 ,Gly 5-ol]-enkephalin (DAMGO) also produced dose-dependent flexor response in same dose ranges. Morphine-induced flexor responses were markedly inhibited by naloxone and d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr amide (CTOP) both MOP-R antagonists and by intrathecal injection of antisense oligodeoxynucleotide (AS-ODN) for MOP-R which is expected to reduce the receptor expression in sensory nerve endings. Prior incubation with capsaicin, a depletor of SP from polymodal C fibers and [(+)-(2S,3S)-(2-methoxybenzylamino)-2-phenylpiperidine] (CP-99994), a tachykinin 1 receptor antagonist, also blocked the morphine-induced flexor responses. Moreover, pertussis toxin (PTX) which inactivates G␣ i/o ; [(1-[6-([(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione)] (U-73122), an inhibitor of phospholipase C (PLC); ethyleneglycol-bis(-aminoethyl ether) N,N,N ,N-tetraacetic acid (EGTA), a Ca 2+ chelating agent; xestospongin C, a membrane-permeable inositol trisphosphate (InsP 3) receptor antagonist inhibited the morphine-flexor responses. However, thapsigargin, a depletor of intracellular Ca 2+ concentration and diphenhydramine, a histamine (His) H1 receptor antagonist, were unable to block the morphine-induced flexor responses. These results suggest that extremely low doses of morphine can stimulate sensory nerve endings through activation of peripheral MOP-R and its downstream mechanisms include activation of PLC through a SP release from polymodal C fibers.
The role of midbrain reticular formation, which includes the nucleus cuneiformis (NCF), as a crucial antinociceptive region in descending pain modulation has long been investigated. In this study, we tried to highlight the role of NCF in morphine-induced antinociception in formalin-induced pain model in rats. Methods: A total of 201 male Wistar rats weighing 260-310 g were used in this study. The effective dose of morphine in systemic administration (intraperitoneal; i.p.) was determined after a dose-and time-response protocol. In consequent groups, bilateral electrolytic lesion (500 μA, 30 sec) or reversible inactivation (lidocaine 2%) were used in the NCF before systemic administration of morphine, and then, the nociceptive test was immediately carried out. Results: The results showed that administration of 6 mg/kg morphine, 30 min before the formalin test, is the best dose-and time-response set in these experiments. The obtained data also indicated that bilateral electrical destruction or reversible inactivation of the NCF significantly decreased antinociceptive responses of systemic morphine (6 mg/kg; i.p.) during the second phase of formalin test (P<0.05). Discussion: Therefore, it seems that opioid receptors located in the NCF may be involved in modulation of central sensitization which occurred in inflammatory pain in rats.
Pain, 1995
We have investigated the role of the endogenous opioid system (EOS) on the inflammatory response induced by subplantar (s.p.) injection of saline (SS) and carrageenan (CA) in the hindpaw of the rat. The administration of intraperitoneal (i.p.) naloxone was used in order to unmask the effects of endogenous opiates released during peripheral inflammation. Three groups of rats received one of the following s.p. treatments: SS, CA, or no injection (NI). Pain pressure threshold (PPT), paw volume (edema) and local temperature were evaluated in baseline conditions and 3 h after treatment. In each group, the effects of i.p. vehicle, naloxone and (+)-naloxone (0.1 mg/kg) were also investigated. Both SS and CA induced a significant inflammatory response with hyperalgesia, edema and local hyperthermia. The i.p. administration of naloxone but not that of (+)-naloxone 15 min prior to testing, significantly increased edema in all groups of treatment (P < 0.05), without altering PPT or local temperature. Two-way ANOVA revealed that treatment and drugs, as well as their interaction, had a significant impact on edema which was related to the effects of CA and naloxone. Our findings illustrate the involvement of the EOS in the physiological response to local injury, regulating microvascular leakage in the inflamed tissues.