n-methylnaloxone and Pain

Opioids are the drugs of choice for treating moderate-to-severe pain, especially for patients in the end stage of cancer or other advanced illnesses, and also in critical care or for the treatment of chronic pain. Side effects such as nausea, pruritus, dizziness and constipation have to be controlled in order to use these drugs to their full potential. Opioid-induced bowel syndrome and constipation caused by activation of μ-receptors in the gut can have such distressing effects that some patients prefer to forego adequate pain control. Methylnaltrexone is a μ-opioid receptor antagonist that, unlike naltrexone or naloxone, does not pass the blood-brain barrier, and therefore does not impair the centrally mediated analgesic effect of opioids. It is licensed for the treatment of opioid-induced constipation in palliative care in more than 50 countries. This article presents practically relevant pharmacological data, basic research results and evidence from clinical research about methylnaltrexone, and outlines potential future therapeutic options for this promising drug.

Topics: Analgesics, Opioid; Constipation; Humans; Naloxone; Narcotic Antagonists; Pain; Palliative Care; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome

Topics: Analgesia; Analgesics, Opioid; Animals; Antigens, Ly; Carrageenan; Female; Inflammation; Macrophages; Mice; Morpholines; Naloxone; Narcotic Antagonists; Neutrophils; Oligopeptides; Pain; Piperazines; Pro-Opiomelanocortin; Pyrazoles; Quaternary Ammonium Compounds; Receptors, sigma; Sigma-1 Receptor

Proopiomelanocortin (POMC)-derived beta-endorphin1-31 from immune cells can inhibit inflammatory pain. Here we investigated cytokine signaling pathways regulating POMC gene expression and beta-endorphin production in lymphocytes to augment such analgesic effects.. Interleukin-4 dose-dependently elevated POMC mRNA expression in naïve lymph node-derived cells in vitro, as determined by real-time PCR. This effect was neutralized by janus kinase (JAK) inhibitors. Transfection of Signal Transducer and Activator of Transcription (STAT) 1/3 but not of STAT6 decoy oligonucleotides abolished interleukin-4 induced POMC gene expression. STAT3 was phosphorylated in in vitro interleukin-4 stimulated lymphocytes and in lymph nodes draining inflamed paws in vivo. Cellular beta-endorphin increased after combined stimulation with interleukin-4 and concanavalin A. Consistently, in vivo reduction of inflammatory pain by passively transferred T cells improved significantly when donor cells were pretreated with interleukin-4 plus concanavalin A. This effect was blocked by naloxone-methiodide.. Interleukin-4 can amplify endogenous opioid peptide expression mediated by JAK-STAT1/3 activation in mitogen-activated lymphocytes. Transfer of these cells leads to inhibition of inflammatory pain via activation of peripheral opioid receptors.

Topics: Animals; Cells, Cultured; Concanavalin A; Inflammation; Interleukin-4; Janus Kinase 3; Lymphocytes; Male; Naloxone; Pain; Pro-Opiomelanocortin; Quaternary Ammonium Compounds; Rats; Rats, Wistar; RNA, Messenger; STAT1 Transcription Factor; STAT3 Transcription Factor

Cannabinoid 2 receptor (CB2R) agonists attenuate inflammatory pain but the precise mechanism implicated in these effects is not completely elucidated. We investigated if the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K(+) (KATP) channels signaling pathway triggered by the neuronal nitric oxide synthase (NOS1) and modulated by opioids, participates in the local antinociceptive effects produced by a CB2R agonist (JWH-015) during chronic inflammatory pain.. In wild type (WT) and NOS1 knockout (NOS1-KO) mice, at 10 days after the subplantar administration of complete Freund's adjuvant (CFA), we evaluated the antiallodynic (von Frey filaments) and antihyperalgesic (plantar test) effects produced by the subplantar administration of JWH-015 and the reversion of their effects by the local co-administration with CB2R (AM630), peripheral opioid receptor (naloxone methiodide, NX-ME) or CB1R (AM251) antagonists. Expression of CB2R and NOS1 as well as the antinociceptive effects produced by a high dose of JWH-015 combined with different doses of selective L-guanylate cyclase (ODQ) or PKG (Rp-8-pCPT-cGMPs) inhibitors or a KATP channel blocker (glibenclamide), were also assessed. Results show that the local administration of JWH-015 dose-dependently inhibited the mechanical and thermal hypersensitivity induced by CFA which effects were completely reversed by the local co-administration of AM630 or NX-ME, but not AM251. Inflammatory pain increased the paw expression of CB2R and the dorsal root ganglia transcription of NOS1. Moreover, the antinociceptive effects of JWH-015 were absent in NOS1-KO mice and diminished by their co-administration with ODQ, Rp-8-pCPT-cGMPs or glibenclamide.. These data indicate that the peripheral antinociceptive effects of JWH-015 during chronic inflammatory pain are mainly produced by the local activation of the nitric oxide-cGMP-PKG-KATP signaling pathway, triggered by NOS1 and mediated by endogenous opioids. These findings suggest that the activation of this pathway might be an interesting therapeutic target for the treatment of chronic inflammatory pain with cannabinoids.

Topics: Analgesics; Analgesics, Opioid; Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cyclic GMP; Glyburide; Indoles; KATP Channels; Mice; Mice, Knockout; Naloxone; Nitric Oxide; Nitric Oxide Synthase Type I; Pain; Piperidines; Pyrazoles; Quaternary Ammonium Compounds; Receptors, Cannabinoid; Signal Transduction; Thionucleotides

The analgesic effect induced by opiates is often potentiated during experimental inflammatory processes. We describe here that lower doses of systemic morphine are necessary to increase thermal withdrawal latencies measured in both hind paws of mice acutely inflamed with carrageenan than in healthy ones. This bilateral potentiation seems mediated through spinal opioid receptors since it is inhibited by the intrathecal (i.t.), but not intraplantar (i.pl.) administration of the opioid receptor antagonist naloxone-methiodide, and also appears when morphine is i.t. administered. Furthermore, the i.pl. administration of the nitric oxide (NO) synthase inhibitor, L-NMMA, or the K (ATP) (+) -channel blocker, glibenclamide, to carrageenan-inflamed mice inhibits the enhanced effect of systemic morphine in the paw that receives the injection of the drug, without affecting the potentiation observed in the contralateral one. The i.pl. administration of L-NMMA also partially antagonised the analgesic effect induced by i.t. morphine in inflamed mice. Finally, the increased analgesic effect evoked by the i.pl. administration of the NO donor SIN-1 either in the inflamed or in the contralateral paw of carrageenan-inflamed mice suggests that enhanced responsiveness to the peripheral analgesic effect of NO may be also underlying the bilateral potentiation of morphine-induced analgesia in acutely inflamed mice.

Topics: Acute Disease; Analgesia; Animals; Carrageenan; Glyburide; Inflammation; Injections, Spinal; Mice; Molsidomine; Morphine; Naloxone; Nociceptors; omega-N-Methylarginine; Pain; Quaternary Ammonium Compounds; Spinal Cord; Temperature

Morphine and methadone are both high-affinity, potent mu-opioid peptide (MOP) receptor analgesics. In this report, we compared the antinociceptive potencies of these 2 drugs when administered subcutaneously (s.c.), intrathecally (i.t.), or intracerebroventricularly (i.c.v.) in both rat and mouse, using the tail-flick assay. We found that both morphine and methadone were potently antinociceptive when the drugs were administered s.c., showing comparable AD50 values in both species. However, the antinociception produced by methadone, when it was administered centrally, was much weaker than that produced by centrally administered morphine. Specifically, the AD50 value for methadone antinociception was more than 30-fold higher at both the i.t. and i.c.v. sites in mouse and not measurable in rat. Naloxone methiodide (NLX-M), a peripherally restricted antagonist, was used to further examine the relative contribution of central versus peripheral sites to morphine and methadone antinociception. NLX-M, when administered s.c., blocked the antinociceptive effect of either systemically or centrally administered methadone but had little effect on the antinociception produced by centrally administered morphine. Furthermore, centrally administered NLX-M significantly blocked antinociception produced by centrally administered morphine but not that produced by centrally administered methadone. Together, these results suggest that methadone antinociception is significantly dependent on an action of the drug at peripheral sites and could provide novel insight into the neural mechanisms that distinguish morphine versus methadone antinociception.. Methadone is often used as an alternative for pain management. The present study shows that a peripheral action plays a crucial role in methadone antinociception. This finding could have significant clinical relevance for the use of methadone versus morphine for the treatment of certain types of pain.

Topics: Analgesics, Opioid; Animals; Drug Administration Routes; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Male; Methadone; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Species Specificity

We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M.I., Callado, L.F., Cano, C., Goya, P., Jagerovic, N. 2002. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71, 1023-1034]. One of them, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (IQMF-4), showed an interesting antinociceptive activity. Intraperitoneally (i.p.) administered, it was as effective as fentanyl or morphine, being less potent than fentanyl but more so than morphine. The aim of the present work was to evaluate its antinociceptive effect by different routes of administration, using the hot plate test, and to investigate possible side effects, such as tolerance and withdrawal, in vitro, using the myenteric plexus-longitudinal muscle strip preparation from guinea pig ileum, and in vivo, using the hot plate test. IQMF-4 was more potent than morphine when administered per os (p.o.), but less potent when administered intracerebroventricularly (i.c.v.). By both routes, fentanyl is more potent that IQMF-4. When IQMF-4 was administered i.p., naloxone methiodide, a peripherally acting antagonist, was able to completely block its antinociceptive effect, whereas, after i.c.v. administration, the blockade was only partial. An interesting feature of the new compound is that it induces tolerance in vitro but not in vivo. Moreover, though in vitro withdrawal was not different from fentanyl or morphine, in vivo withdrawal symptoms were significantly less frequent in mice treated with IQMF-4 than in those treated with morphine or fentanyl. Although more assays are required, these results show that IQMF-4 appears to be a potent analgesic compound with an interesting peripheral component, and reduced ability to induce dependence.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Fentanyl; Guinea Pigs; Hot Temperature; Ileum; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Measurement; Pain Threshold; Piperidines; Propane; Quaternary Ammonium Compounds; Reaction Time; Substance Withdrawal Syndrome; Time Factors

A visceral pain model incorporating use of cyclophosphamide (CP) to induce bladder inflammation has been described. CP treatment in rats produces changes in behavior (abnormal postures and eye closure) and respiration rate indicative of visceral pain. We characterized the dose-dependency and progression of CP-induced cystitis pain after intraperitoneal (i.p.) CP. The behavioral and respiration rate changes were ameliorated by systemic morphine and ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine], a neuronal nicotinic acetylcholine receptor agonist, in a manner reversible by naloxone and mecamylamine, respectively. Sites of antinociceptive actions of morphine and ABT-594 were investigated using systemic, intrathecal (i.t.), or intracerebroventricular (i.c.v.) administration of blood-brain barrier impenetrant antagonists. Naloxone methiodide produced a complete antagonism of morphine antinociception after i.c.v. but not i.p. or i.t. administration. Chlorisondamine blocked ABT-594 antinociception after i.c.v. but not i.p. administration. Further pharmacological characterization of behavioral and respiration changes in CP-cystitis was performed using standard analgesics. The alpha(2)-adrenoceptor agonist clonidine produced a weak attenuation of CP-pain behavior. NSAIDs (ibuprofen, acetaminophen, and celecoxib) and anticonvulsants (gabapentin and lamotrigine) were without effect. These results demonstrate that morphine and ABT-594 produce antinociception in CP-cystitis by a predominantly supraspinal site of action, and that mechanisms producing robust centrally-mediated antinociception could be beneficial in cystitis pain.. In this article, potential antinociceptive effects of a variety of pharmacological agents were evaluated in a rat cystitis pain model. Morphine and a nicotinic acetylcholine receptor agonist ABT-594 were found to exert potent antinociception in this model. Findings presented here aid identification of agents to treat cystitis pain in the clinic.

Topics: Analgesics; Animals; Azetidines; Behavior, Animal; Brain; Chlorisondamine; Cyclophosphamide; Cystitis; Disease Models, Animal; Male; Mecamylamine; Morphine; Naloxone; Narcotic Antagonists; Nicotinic Antagonists; Pain; Pyridines; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Viscera

It has been shown that acupuncture relieves symptoms of abdominal pain and bloating in patients with irritable bowel syndrome (IBS). However, the mechanism of beneficial effects of acupuncture still remains unproven. The aim of the present study was to investigate the mechanisms of the antinociceptive effects of acupuncture in conscious dogs. We evaluated the increase in mean arterial blood pressure (MAP) caused by rectal distension as an index of visceral pain. Electroacupuncture (EA; 10 Hz) at ST-36 (lower leg), but not at BL-21 (back), significantly reduced the increase in MAP in response to rectal distension (30 and 40 cm3). The antinociceptive effect of EA at ST-36 was abolished by pretreatment with naloxone (a central and peripheral opioid receptor antagonist) but not by naloxone methiodide (a peripheral opioid receptor antagonist). These results suggest that EA at ST-36 may reduce visceral pain via central opioid pathway. Acupuncture may be useful to treat visceral hypersensitivity in IBS patients.

Topics: Animals; Back; Blood Pressure; Catheterization; Dogs; Electroacupuncture; Female; Hindlimb; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Quaternary Ammonium Compounds; Rectal Diseases; Viscera

Previous reports have shown that systemic administration of morphine can prevent the thermal hyperalgesia induced by the development of an osteosarcoma in C3H/HeJ mice after the implantation of NCTC 2472 cells. We show here that this type of hyperalgesia is also abolished by the local administration of morphine given at low doses (10 nmol), or the peripheral acting opioid receptor agonist loperamide (146 nmol). The analgesic effect of loperamide is prevented by the administration of the opioid receptor antagonist naloxone methiodide (10 mg/kg, i.p.), which is unable to cross the blood-brain barrier. These results provide evidence which supports the fact that peripheral opioids could be useful tools in the management of some types of cancer pain.

Topics: Analgesics, Opioid; Animals; Bone Neoplasms; Cell Culture Techniques; Hyperalgesia; Loperamide; Mice; Mice, Inbred C3H; Morphine; Naloxone; Narcotic Antagonists; Osteosarcoma; Pain; Quaternary Ammonium Compounds

1. The anti-nociceptive effects of contralateral administration of kappa-opioid agonist U-50,488H were investigated in rats. 2. Inflammation was induced by unilateral injection of 1% carrageenan into the right hindpaw. Prior to carrageenan injection, U-50,488H or saline was administered into the left hindpaw. Withdrawal responses to mechanical and heat stimulation and oedema levels were evaluated at 3, 6 and 24 h post-carrageenan injection. 3. The results showed that the inflammatory effect of 1% carrageenan peaked after 6 h with bilateral decreases in withdrawal latencies and ipsilateral oedema formation. 4. Contralateral treatment with 0.01, 0.05, 0.3 and 2 mg of U-50,488H attenuated nociceptive reflexes to mechanical stimulation on the inflamed side at 6 h. The anti-nociceptive effect of contralateral treatment was dose-dependent at 3 and 24 h. The hindpaw withdrawal latencies to heat stimulation were prolonged at 3 and 24 h after contralateral treatment with 0.3 mg U-50,488H. No effect on inflammatory oedema formation was observed, except for a decrease at 3 h after treatment with 2 mg of U-50,488H. 5. Sciatic nerve denervation on the contralateral side abolished the anti-nociceptive effects of U-50,488H (0.3 and 2 mg). In contrast, contralateral injection of 1 mg morphine prolonged paw latencies in denervated rats. 6. Both co-administration of the peripherally selective opioid antagonist naloxone methiodide with 0.3 mg U-50,488H, and alternatively, systemic administration of 0.3 mg U-50,488H reversed the anti-nociceptive effects induced by contralateral injection of U-50,488H. 7. Taken together, our findings indicate that the contralateral administration of U-50,488H attenuates nociceptive behaviour resulting from acute inflammation. The effect is mediated via peripheral neuronal kappa-opioid receptors and, possibly, spinal cord mechanisms, suggesting a new treatment approach for acute inflammatory conditions.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acute Disease; Analgesics, Opioid; Animals; Behavior, Animal; Denervation; Hindlimb; Hot Temperature; Inflammation; Male; Naloxone; Pain; Pain Measurement; Physical Stimulation; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sciatic Nerve

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

Topics: Analgesia; Animals; Arteries; Blood Pressure; Body Temperature; Body Weight; Brain; Chronic Disease; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Injection of dilute formalin into the hindpaw produces brief (phase 1) and persistent (phase 2) nociceptive responses in the rat. We recently reported that ongoing peripheral nerve input is required for the expression of behavioral and cardiovascular responses during phase 2. Here we evaluated the contribution of central and peripheral sensitization mechanisms, generated during phase 1, to the magnitude and temporal profile of phase 2. During phase 1, we administered analgesic doses of an ultrashort-acting opioid, remifentanil (i.v. administration from 0-5 min after 5.0% formalin injection), or anesthetic concentrations of halothane (2.1%). Inhibition of phase 1 did not reduce the magnitude of flinching and cardiovascular responses during phase 2, but it did delay their onset and/or termination. Longer remifentanil infusions (0-15 or 0-30 min) produced even longer delays (up to 30 min) in the onset and termination of flinching during phase 2; however, when remifentanil was administered during the early part of phase 2 (15-30 or 15-45 min), it did not prolong the time to termination of phase 2. Continuous infusion (10 mg/kg/hr i.v.) of a peripherally acting opiate antagonist, naloxone methiodide, did not reduce the antinociception produced by remifentanil during phase 1 but almost completely reversed the delay in the onset and termination of phase 2. We conclude that central sensitization mechanisms during phase 1 do not influence the magnitude of phase 2. We also hypothesize that remifentanil interacts with peripheral opioid receptors to impede the formalin-evoked synthesis and/or release of proinflammatory compounds during phase 1 and thus delay phase 2.

Topics: Analgesics, Opioid; Analysis of Variance; Anesthesia, Inhalation; Animals; Blood Pressure; Formaldehyde; Halothane; Heart Rate; Injections, Intravenous; Male; Naloxone; Pain; Piperidines; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Remifentanil; Time Factors

RB101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-ox-opropyl)-L-phenylalanine benzyl ester) is a recently developed full inhibitor of the enkephalin-catabolizing enzymes able to cross the blood-brain barrier, whereas RB38A ((R)-3-(N-hydroxycarboxamido-2-benzylpropanoyl)-L-phenylalanine) is as potent as RB101 but almost unable to enter the brain. In this study, we have investigated the effects of systemic administration of morphine, RB101 and RB38A on nociception induced by pressure on inflamed peripheral tissues. Antinociceptive test was performed between 4 and 5 days after injection into the rat left hindpaw of Freund's complete adjuvant to produce localized inflammation. Morphine (1, 2 and 4 mg/kg, i.v.) induced antinociception in inflamed paws at all the doses used, and only at the highest dose in non-inflamed paws. RB101 (10 and 20 mg/kg, i.v.) induced an antinociceptive response only in the inflamed paws. RB38A, also induced an antinociceptive effect in the inflamed paws, but only at the highest dose (20 mg/kg, i.v.). The responses induced by morphine and the inhibitors of enkephalin catabolism were antagonized by the systemic administration of naloxone (1 mg/kg) or methylnaloxonium (2 mg/kg) which acts essentially outside the brain. Central injection (i.c.v.) of methylnaloxonium (2 micrograms) blocked the effect of morphine only in non-inflamed paws, and slightly decreased the response induced by RB101 on inflamed paws. These results indicate that the endogenous opioid peptides, probably enkephalins, are important in the peripheral control of nociception from inflamed tissues.

Topics: Analgesics; Animals; Disulfides; Enkephalins; Hydroxamic Acids; Inflammation; Injections, Intraventricular; Male; Morphine; Naloxone; Narcotic Antagonists; Neprilysin; Pain; Pain Measurement; Phenylalanine; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley