Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine and κ-opioid receptors in rat spinal cord nociceptive reflexes.

Antinociception induced by the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is linked to opioid receptors. We studied the subtype of receptors to which CPA action is related, as well as a possible enhancement of antinociception when CPA is coadministered with opioid receptor agonists. Spinal cord neuronal nociceptive responses of male Wistar rats with inflammation were recorded using the single motor unit technique. CPA antinociception was challenged with naloxone or norbinaltorphimine. The antinociceptive activity of fentanyl and U-50488H was studied alone and combined with CPA. Reversal of CPA antinociception was observed with norbinaltorphimine (82.9±13% of control) but not with low doses of naloxone (27±8% of control), indicating an involvement of κ-opioid but not µ-opioid receptors. Low doses of CPA did not modify fentanyl antinociception. However, a significant enhancement of the duration of antinociception was seen when U-50488H was coadministered with CPA. We conclude that antinociception mediated by CPA in the spinal cord is associated with activation of κ-opioid but not µ-opioid receptors in inflammation. In addition, coadministration of CPA and κ-opioid receptor agonists is followed by significantly longer antinociception, opening new perspectives in the treatment of chronic inflammatory pain.

Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and opioid receptors in spinal cord nociceptive reflexes.

AIMS: We previously observed that the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is a very effective antinociceptive agent on intact but not on spinalized adult rats with inflammation. Since a close connection between opioid and adenosine A1 receptors has been described, we studied a possible relationship between these systems in the spinal cord. MAIN METHODS: CPA-mediated antinociception was challenged by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) and by the opioid receptor antagonist naloxone on male adult Wistar rats with carrageenan-induced inflammation. Withdrawal reflexes activated by noxious mechanical and electrical stimulation were recorded using the single motor technique in intact and sham-spinalized animals. KEY FINDINGS: CPA was very effective in intact and sham spinalized rats but not in spinalized animals. Full reversal of CPA antinociception was observed with i.v. 1mg/kg of naloxone but not with 20mg/kg of CPT i.v. in responses to noxious mechanical and electrical stimulation. CPT fully prevented CPA from any antinociceptive action whereas naloxone did not modify CPA activity. These results suggest a centrally-mediated action, since CPA depressed the wind-up phenomenon which is derived of the activity of spinal cord neurons. SIGNIFICANCE: The present study provides strong in vivo evidence of an antinociceptive activity mediated by the adenosine A1 receptor system in the spinal cord, linked to an activation of opioid receptors in adult animals with inflammation.

Subeffective doses of nitroparacetamol (NCX-701) enhance the antinociceptive activity of the α2-adrenoceptor agonist medetomidine.

The α2-adrenergic system is involved in pain processing and inflammation-induced sensitization. α2-adrenoceptor agonists induce analgesia, and this effect is greater when administered in combination with other analgesics. In the present study, we assessed a possible enhancement of antinociception combining the α2-adrenoceptor agonist medetomidine with subeffective doses of NCX701 (nitroparacetamol). The effects of the drugs were studied in spinal cord neuronal responses from adult male Wistar rats with carrageenan-induced inflammation, using the recording of single motor unit technique. The experiments showed that the i.v. administration of medetomidine and NCX701 induced a more potent and effective antinociceptive effect than medetomidine when given alone (ID50: 0.47±0.1 vs. 1.1±0.1 µg/kg) or in the presence of paracetamol, in naturally-evoked nociceptive responses. In addition, the duration of antinociception was significantly longer (P<0.001, 100 min after administration). The use of low doses of NCX701 and α2-adrenoceptor agonists might open new perspectives in the treatment of inflammatory pain.

Antinociceptive effects of NCX-701 (nitro-paracetamol) in neuropathic rats: enhancement of antinociception by co-administration with gabapentin.

BACKGROUND AND PURPOSE: Neuropathic pain is characterized by a poor response to classic analgesics. In the present study, we have assessed the antinociceptive activity of NCX-701 (nitro-paracetamol) in neuropathic rats, after systemic and intrathecal (i.t.) administration. In addition, we analysed the possible benefit of the combination of NCX-701 and gabapentin, a well-known potent analgesic, in the treatment of neuropathic pain. EXPERIMENTAL APPROACH: The antinociceptive effects of i.v. and i.t. NCX-701 and paracetamol were studied in spinal cord neuronal responses from neuropathic adult male Wistar rats, using the recording of single motor units technique. The effect of i.v. and i.t. NCX-701 in combination with i.v. gabapentin was studied by isobolographic analysis. KEY RESULTS: The experiments showed that NCX-701, but not paracetamol, dose-dependently reduced the nociceptive responses evoked by noxious mechanical and electrical stimulation, after i.v. (ID(50) 542 +/- 5 micromol kg(-1) for noxious mechanical stimulation) or i.t. (ID(50) 932 +/- 16 nmol kg(-1)) administration. The combined administration of i.v. or i.t. NCX-701 and i.v. gabapentin induced a more intense antinociceptive effect than any of the two drugs given alone. The isobolographic analysis showed a synergistic effect. CONCLUSIONS AND IMPLICATIONS: NCX-701 is an effective antinociceptive compound in situations of neuropathy-induced sensitization, with an action mainly located in the spinal cord. The combination of NCX-701 and gabapentin induces a synergistic enhancement of the depression of nociceptive responses evoked by natural noxious stimulation. The use of NCX-701 alone or in combination with gabapentin might open up new and promising perspectives in the treatment of neuropathic pain.

NCX 2057, a novel NO-releasing derivative of ferulic acid, suppresses inflammatory and nociceptive responses in in vitro and in vivo models.

BACKGROUND AND PURPOSE: We previously reported that NCX 2057, a compound comprising a nitric oxide (NO)-releasing moiety and the natural antioxidant, ferulic acid (FA), inhibits pro-inflammatory mediators through NO-mediated gene regulation. Here, we have assessed the activities of NCX 2057 in models of inflammatory and neuropathic pain, and characterized its effects on cyclooxygenase (COX)-1 and COX-2. EXPERIMENTAL APPROACH: Anti-nociceptive and anti-inflammatory activities of NCX 2057 were measured in vitro and in vivo in models of inflammatory (carrageenan) and neuropathic (chronic constriction injury; CCI) pain. Effects of NCX 2057 were measured on COX-1 and COX-2 activities in RAW 264.7 macrophages. KEY RESULTS: NCX 2057 dose-dependently inhibited single motor unit responses to noxious mechanical stimulation (ID(50)= 100 micromol kg(-1)) and wind-up responses in rats with paw inflammation induced by carrageenan. Moreover, NCX 2057 inhibited allodynic responses following CCI of the sciatic nerve [ipsilateral Paw Withdrawal Threshold (g): vehicle: 41.4 +/- 3.3; NCX 2057: 76.3 +/- 4.8 FA: 37.9 +/- 15.5 at 175 micromol kg(-1)]. NCX 2057 reversed carrageenan-induced hyperalgesic responses in mice and inhibited prostaglandin E(2) formation in paw exudates. Finally, NCX 2057 competitively inhibited COX-1 and COX-2 activities in whole RAW macophages (IC(50)= 14.7 +/- 7.4 and 21.6 +/- 7.5 microM, respectively). None of these properties were exhibited by equivalent treatments with FA or standard NO donor compounds. CONCLUSIONS AND IMPLICATIONS: These studies indicate that NCX 2057 is effective in chronic inflammatory and neuropathic pain models, probably because of its particular combination of anti-COX, antioxidant and NO-releasing properties.

Nitroparacetamol (NCX-701) and pain: first in a series of novel analgesics.

The combination of numerous classic drugs with nitric oxide donors has led to the development of new compounds with promising therapeutic activities in a great variety of situations, including cardiovascular and respiratory systems, ocular pressure, inflammation, and pain. One of the first compounds developed was NCX-701 or nitroparacetamol, resulting from the combination of paracetamol, a classic and popular analgesic used in a great number of over-the-counter medications because of its antipyretic and analgesic properties, and a nitrooxybutyroyl moiety, which releases nitric oxide at a low but steady level. Although paracetamol is devoid of most of the gastrointestinal toxicity associated with aspirin-like drugs, this type of compounds was first designed to take advantage of the cytoprotective properties of nitric oxide when released at low concentrations. However, the combination of these molecules also resulted in an unexpected enhancement of the analgesic activity of paracetamol. In fact, NCX-701 has been shown to be effective in acute nociception as well as in neuropathic pain, situations in which paracetamol and other COX inhibitors are devoid of any effect. In addition, NCX-701 is more potent and, in some circumstances, more effective than its parent compound in different models of inflammatory pain. Furthermore, whereas paracetamol lacks any effective antiinflammatory action, NCX-701 might reduce inflammation. All these results taken together imply that the mechanism of action of NCX-701 is different from that of paracetamol, although it is not yet established for either molecule. NCX-701 appears to be a promising compound in the treatment of different types of pain, with a likely better profile of side effects than its parent molecule, paracetamol. Although recent clinical trials provided data consistent with the preclinical profile of NCX-701, further studies are needed to support its clinical use.

The antinociceptive effect of systemic gabapentin is related to the type of sensitization-induced hyperalgesia.

BACKGROUND: Gabapentin is a structural analogue of gamma-aminobutyric acid with strong anticonvulsant and analgesic activities. Important discrepancies are observed on the effectiveness and potency of gabapentin in acute nociception and sensitization due to inflammation and neuropathy. There is also some controversy in the literature on whether gabapentin is only active in central areas of the nervous system or is also effective in the periphery. This is probably due to the use of different experimental models, routes of administration and types of sensitization. The aim of the present study was to investigate the influence of the spinal cord sensitization on the antinociceptive activity of gabapentin in the absence and in the presence of monoarthritis and neuropathy, using the same experimental protocol of stimulation and the same technique of evaluation of antinociception. METHODS: We studied the antinociceptive effects of iv. gabapentin in spinal cord neuronal responses from adult male Wistar rats using the recording of single motor units technique. Gabapentin was studied in the absence and in the presence of sensitization due to arthritis and neuropathy, combining noxious mechanical and repetitive electrical stimulation (wind-up). RESULTS: The experiments showed that gabapentin was effective in arthritic (max. effect of 41 +/- 15% of control and ID50 of 1,145 +/- 14 micromol/kg; 200 mg/kg) and neuropathic rats (max. effect of 20 +/- 8% of control and ID50 of 414 +/- 27 micromol/kg; 73 mg/kg) but not in normal rats. The phenomenon of wind-up was dose-dependently reduced by gabapentin in neuropathy but not in normal and arthritic rats. CONCLUSION: We conclude that systemic gabapentin is a potent and effective antinociceptive agent in sensitization caused by arthritis and neuropathy but not in the absence of sensitization. The potency of the antinociception was directly related to the intensity of sensitization in the present experimental conditions. The effect is mainly located in central areas in neuropathy since wind-up was significantly reduced, however, an action on inflammation-induced sensitized nociceptors is also likely.

All-trans retinoic acid induces COX-2 and prostaglandin E2 synthesis in SH-SY5Y human neuroblastoma cells: involvement of retinoic acid receptors and extracellular-regulated kinase 1/2.

BACKGROUND: Our recent results show that all-trans retinoic acid (ATRA), an active metabolite of vitamin A, induces COX-dependent hyperalgesia and allodynia in rats. This effect was mediated by retinoic acid receptors (RARs) and was associated with increased COX-2 expression in the spinal cord. Since ATRA also up-regulated COX-2 expression in SH-SY5Y human neuroblastoma cells, the current study was undertaken to analyze in these cells the mechanism through which ATRA increases COX activity. METHODS: Cultured SH-SY5Y neuroblastoma cells were treated with ATRA. COX expression and kinase activity were analyzed by western blot. Transcriptional mechanisms were analyzed by RT-PCR and promoter assays. Pharmacological inhibitors of kinase activity and pan-antagonists of RAR or RXR were used to assess the relevance of these signaling pathways. Production of prostaglandin E2 (PGE2) was quantified by enzyme immunoabsorbent assay. Statistical significance between individual groups was tested using the non-parametric unpaired Mann-Whitney U test. RESULTS: ATRA induced a significant increase of COX-2 expression in a dose- and time-dependent manner in SH-SY5Y human neuroblastoma cells, while COX-1 expression remained unchanged. Morphological features of differentiation were not observed in ATRA-treated cells. Up-regulation of COX-2 protein expression was followed by increased production of PGE2. ATRA also up-regulated COX-2 mRNA expression and increased the activity of a human COX-2 promoter construct. We next explored the participation of RARs and mitogen-activated peptide kinases (MAPK). Pre-incubation of SH-SY5Y human neuroblastoma cells with either RAR-pan-antagonist LE540 or MAP kinase kinase 1 (MEK-1) inhibitor PD98059 resulted in the abolition of ATRA-induced COX-2 promoter activity, COX-2 protein expression and PGE2 production whereas the retinoid X receptor pan-antagonist HX531, the p38 MAPK inhibitor SB203580 or the c-Jun kinase inhibitor SP600125 did not have any effect. The increase in RAR-beta expression and extracellular-regulated kinase 1/2(ERK1/2) phosphorylation in ATRA-incubated cells suggested that RARs and ERK1/2 were in fact activated by ATRA in SH-SY5Y human neuroblastoma cells. CONCLUSION: These results highlight the importance of RAR-dependent and kinase-dependent mechanisms for ATRA-induced COX-2 expression and activity.

Enhancement of the analgesic activity of paracetamol and nitroparacetamol by the oral administration of all-trans retinoic acid.

All-trans retinoic acid (ATRA), the active metabolite of vitamin A, is involved in the inflammatory reaction and modulates the expression of cyclooxygenase (COX) enzymes and nitric oxide (NO) activity. Since COX enzymes are the substrate of action of COX inhibitors, we studied the analgesic activity of paracetamol (PAR) and its NO-derivative nitroparacetamol (NOP) in the presence and absence of oral ATRA. Nociceptive responses were studied using the recording of single motor units technique in alpha-chloralose anesthetized normal and monoarthritic male Wistar rats. Intravenous PAR was not effective in normal rats. However, after pre-treatment with ATRA, PAR reduced dose-dependently the responses to noxious mechanical stimulation (ID50: 60+/-7 micromol/kg; 9.1 mg/kg), but not wind-up. The analgesic activity of NOP was enhanced after pre-treatment with ATRA either on responses to noxious mechanical stimulation (ID50s: 147+/-2 vs. 46+/-2 micromol/kg) or wind-up (maximal effect of 46+/-1% with 480 micromol/kg vs. 33+/-3% of control with 240 micromol/kg). The administration of ATRA did not modify the effect of PAR and NOP in monoarthritic rats. We conclude that pre-treatment with oral ATRA enhances the analgesic activity of PAR and NOP in acute pain, probably due to a positive modulation of their activity on spinal cord COX enzymes.

The influence of the time course of inflammation and spinalization on the antinociceptive activity of the alpha2-adrenoceptor agonist medetomidine.

The purpose of the present study was to investigate the influence of the time course of inflammation and the implication of spinal and supraspinal sites on the antihyperalgesic effects of the alpha(2)-adrenoceptor agonist medetomidine. Behavioral experiments showed a more intense antihyperalgesia in the phase of maintenance of inflammation than in the early or resolution stages. Maximum effect, without sedation, was observed with a dose of 40 microg/kg (66+/-12% and 76+/-15% reduction of mechanical and thermal hyperalgesia). No change was observed in the paw swelling, indicating that its effects were not secondary to a reduction of inflammation. In electrophysiological experiments, the effect was more pronounced in animals with an intact spinal cord than in spinalized animals (max. effects of 2+/-0.7% vs. 48+/-11% of control, noxious mechanical stimulation). We conclude that the antihyperalgesic effect of medetomidine depends on the time course of inflammation and that it is mainly located supraspinally.

Enhancement of wind-up by the combined administration of adenosine A1 receptor ligands on spinalized rats with carrageenan-induced inflammation.

The adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is very effective in reducing wind-up in intact but not in spinalized adult rats with carrageenan-induced inflammation, suggesting an adenosine-mediated supraspinal modulation. Since wind-up is a spinal cord mediated phenomenon but highly influenced by descending modulatory systems, especially in situations of sensitization, we assessed the possible involvement of adenosine in the modulation of wind-up. We studied the effect of the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) in the presence and in the absence of the adenosine A(1) receptor agonist CPA. The experiments were carried out in spinalized male Wistar rats under alpha-chloralose anaesthesia. Withdrawal reflexes, studied as single motor units, were activated by noxious mechanical and high-intensity repetitive electrical stimulation (wind-up). While CPA and CPT were not able to induce any change on wind-up when injected alone, the combination of the two drugs, in any order, lead to an important enhancement of wind-up. This enhancement not always paralleled an increase of responses to noxious mechanical stimulation, indicating that the effect is mainly located in the spinal cord. In addition, the enhancement of wind-up was not further increased by the administration of the opioid receptor antagonist naloxone. We conclude that the depression of the wind-up phenomenon observed in spinalized animals is, at least in part, dependent of adenosine systems and can be relieved by the combined administration of CPA and CPT.

Enhancement of fentanyl antinociception by subeffective doses of nitroparacetamol (NCX-701) in acute nociception and in carrageenan-induced monoarthritis.

We have reported that subanalgesic doses of new generation non-steroidal anti-inflammatory drugs (NSAIDs) enhance the antinociceptive activity of the mu-opiate fentanyl, and the duration of its effect, in acute nociception. Since this therapy is intended for situations of hyperalgesia, we have compared the antinociceptive activity of fentanyl in the absence and in the presence of subeffective doses of NCX-701 (nitroparacetamol) in normal animals and in animals with carrageenan-induced monoarthritis. Subanalgesic dose of NCX-701 did not modify any of the nociceptive responses on its own but reduced the ID50 of fentanyl more than two-fold in both the normal and sensitized states. When administered alone, full recovery from fentanyl was always observed within 15 to 20 minutes, however, full recovery was not observed in the presence of NCX-701. Naloxone was unable to reverse the effect, suggesting a possible reduction of other opiate-mediated secondary effects. We therefore studied the possibility that combining administration of fentanyl and nitroparacetamol (NCX-701) would reduce the development of acute tolerance to fentanyl in behavioral experiments. Acute tolerance to fentanyl in behavioral nociceptive reflexes was developed within 72 h after the constant infusion of the drug, whereas in animals treated with small doses of NCX-701 tolerance was not observed. In summary, our results, both in normal animals and in animals with hyperalgesia, show that fentanyl antinociception can be strongly potentiated with subanalgesic doses of the NSAID NCX-701 and that the development of acute tolerance to fentanyl in normal animals is prevented by this combination of drugs.

Subanalgesic doses of dexketoprofen and HCT-2037 (nitrodexketoprofen) enhance fentanyl antinociception in monoarthritic rats.

Subanalgesic doses of the non-steroidal antiinflammatory drugs (NSAID) dexketoprofen trometamol and nitroparacetamol (NCX-701) enhance mu-opiate fentanyl effect in acute nociception. It is not known if a similar combination of drugs is effective in situations of spinal cord sensitization. The aim of this study was to assess if the enhancement of fentanyl antinociception can be observed in carrageenan-induced monoarthritis, when combined with dexketoprofen (DKT) or nitrodexketoprofen (HCT-2037). Withdrawal reflexes were recorded as single motor units in male Wistar rats anesthetized with alpha-chloralose. Fentanyl was studied alone and in the presence of 0.4, 0.8 micromol/kg of DKT or 0.3 micromol/kg of HCT-2037. In responses to noxious mechanical stimulation, the ID50 of fentanyl was enhanced twofold by 0.8 micromol/kg DKT and more than fourfold by HCT-2037 and no significant recovery was observed 45 min later. DKT 0.4 micromol/kg was, however, very little effective. The opioid antagonist naloxone did not reverse the effect. Enhancement of fentanyl effect on wind-up was only observed with HCT-2037 but not with DKT. We conclude that the combined administration of subanalgesic doses of dexketoprofen derivatives, specially its nitroderivative, and the mu-opiate fentanyl is an effective antinociceptive therapy in situations of articular inflammation involving a naloxone-independent mechanism of action.

The antinociceptive effects of the systemic adenosine A1 receptor agonist CPA in the absence and in the presence of spinal cord sensitization.

Adenosine A1 receptor agonists are effective antinociceptive agents in neuropathic and inflammatory pain, though they appear to be weak analgesics in acute nociception. Important discrepancies are observed on the effectiveness and potency of adenosine analogues when comparing different studies, probably due to the use of different ligands, models of antinociception, routes of administration and types of sensitization. We studied the systemic antinociceptive effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) in spinal cord neuronal responses from adult male rats in acute nociception and in sensitization due to arthritis and neuropathy. The experiments showed that CPA was effective in the three experimental conditions, with a similar potency in reducing responses to noxious mechanical stimulation (ID50s: 20 +/- 1.2 microg/kg in acute nociception, 18 +/- 1.1 microg/kg in arthritis, 17.4 +/- 2 microg/kg in neuropathy). The phenomenon of wind-up was also dose-dependently reduced by CPA in the three experimental situations although the main action was seen in arthritis. Depression of blood pressure by CPA was not dose-dependent. We conclude that systemic CPA is a potent and effective analgesic in sensitization due to arthritis and neuropathy but also in acute nociception. The effect is independent of the cardiovascular activity and is centrally mediated since wind-up was inhibited.

Comparison of the antinociceptive activity of two new NO-releasing derivatives of the NSAID S-ketoprofen in rats.

1 Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes inducing analgesic, anti-inflammatory and antipyretic actions. They are not devoid of severe side effects and so, the search for new compounds with similar or higher effectiveness and a lower incidence of undesired actions is important. Nitric oxide (NO)-releasing NSAIDs resulted from this search. 2 We have compared the antinociceptive effectiveness of cumulative doses of two new NO-releasing derivatives of S-ketoprofen, HCT-2037 and HCT-2040, using the recording of spinal cord nociceptive reflexes in anesthetized and awake rats and after intravenous and oral administration. 3 S-ketoprofen and HCT-2040 were equieffective in reducing responses to noxious mechanical stimulation after i.v. administration in anesthetized animals (ID50s: 1.3+/-0.1 and 1.6+/-0.2 micromol kg(-1) respectively), but did not modify wind-up. HCT-2037 was two-fold more potent (ID50 of 0.75+/-0.1 micromol kg(-1)) in responses to mechanical stimuli and very effective in reducing wind-up (63+/-17% of control; P<0.01; MED: 0.4 micromol kg(-1)), indicating a greater activity than the parent compound. 4 In awake animals with inflammation, HCT-2037 p.o. fully inhibited mechanical allodynia, 91+/-12% reduction, and hyperalgesia, 94+/-8% reduction. Equivalent doses of S-ketoprofen only partially reduced either allodynia (50+/-11%) or hyperalgesia (40+/-4%). The effect on responses to noxious thermal stimulation was similar for the two compounds. 5 We conclude that the molecular changes made in the structure of S-ketoprofen including an NO moiety in its structure, improve the antinociceptive profile of the compound opening new perspectives in a safer use of NSAIDs as analgesic drugs.

Spinal vs. supraspinal antinociceptive activity of the adenosine A(1) receptor agonist cyclopentyl-adenosine in rats with inflammation.

The adenosine A(1) receptor is involved in spinal cord antinociception. As its role at supraspinal sites is not well known, we studied the systemic effects of its agonist N-cyclopentyl-adenosine (CPA) in single motor units from adult-spinalized, intact and sham-spinalized rats. CPA was not effective after spinalization, but it was very effective in intact animals (ID50: 92+/-1.3 microg/kg, noxious pinch) and over 10-fold more potent in sham-spinalized animals (ID50 of 8.3+/-1 microg/kg). Wind-up was also inhibited by CPA. We also studied the effect of CPA in the immature spinal cord preparation, where CPA dose-dependently inhibited responses to low (IC50s: 9+/-0.7 and 7.7+/-1.3 nM) and high intensity stimulation (IC50s: 4.9+/-0.5 and 12.1+/-2 nM). We conclude that the integrity of the spinal cord is crucial for the antinociceptive activity of systemic CPA in adult rats but not in immature rats, not yet influenced by a completely developed supraspinal control.

Low doses of nitroparacetamol or dexketoprofen trometamol enhance fentanyl antinociceptive activity.

We have reported that subeffective doses of the nonsteroidal anti-inflammatory drug (NSAID) dexketoprofen trometamol enhances micro-opioid receptor agonist fentanyl antinociception. The aim of this study was to assess if this effect can also be observed with other new cyclooxygenase-inhibitors such as nitroparacetamol, and in responses to high intensity electrical stimulation (wind-up). Single motor units were recorded in male Wistar rats under alpha-chloralose anaesthesia. The antinociceptive effect of fentanyl was studied alone and in the presence of subeffective doses of dexketoprofen trometamol or nitroparacetamol. In responses to noxious mechanical stimulation, the potency of fentanyl was enhanced by more than threefold in the presence of the NSAIDs and no significant recovery was observed after 45 min. The opioid antagonist naloxone and the alpha(2)-adrenoceptor antagonist atipamezol did not reverse the effect. The enhancement of the effect of fentanyl in wind-up was lower though significant. We conclude that the co-administration of subeffective doses of new cyclooxygenase-inhibitors and the micro-opioid receptor agonist fentanyl should be considered as a potential pain therapy.

Antinociception and the new COX inhibitors: research approaches and clinical perspectives.

New generations of cyclooxygenase (COX) inhibitors are more potent and efficacious than their traditional parent compounds. They are also safer than the classic non-steroidal anti-inflammatory drugs (NSAIDs) and are starting to be used not only for low to moderate intensity pain, but also for high intensity pain. Three different strategies have been followed to improve the pharmacological profile of COX inhibitors: 1. Development of COX-2 selective inhibitors. This is based on the initial hypothesis that considered COX-2 as the enzyme responsible for the generation of prostaglandins only in inflammation, and, therefore, uniquely responsible for inflammation, pain and fever. Initial expectations gave rise to controversial results, still under discussion. The second generation of these compounds is being developed and should contribute to clarifying both their efficacy and the specific functions of the COX enzymes. 2. Modified non-selective COX inhibitors. Molecules like nitro-NSAIDs or tromethamine salt derivatives have been synthesized considering that both COX-1 and COX-2 are responsible for the synthesis of prostaglandins involved either in homeostatic functions or inflammation. Nitroaspirin, nitroparacetamol or dexketoprofen trometamol are some examples of molecules that are already showing an important clinical efficacy. The modifications performed in their structures seem to lower the unwanted side effects as well as to enhance their analgesic efficacy. 3. Combined therapy of classic NSAIDs with other drugs. This strategy looks for improvements in the incidence of adverse effects or to take advantage of the synergistic enhancement of their therapeutic effects. Some of the molecules resulting from these strategies are very valuable as therapeutic agents and open a wide range of possibilities in the treatment of high intensity pain, including neuropathic pain, and opiate sparing therapy.

The effects of sham and full spinalization on the antinociceptive effects of NCX-701 (nitroparacetamol) in monoarthritic rats.

Nitric oxide (NO)-releasing NSAIDs have been shown to be safer and more potent as antinociceptive and anti-inflammatory agents than their parent compounds. NCX-701 (nitroparacetamol), in contrast to paracetamol, is an effective antinociceptive drug in normal animals but their effectiveness in monoarthritis has not been compared. We have now investigated this question by comparing the antinociceptive effects of i.v. NCX-701 and paracetamol in monoarthritic rats under alpha-chloralose anesthesia. The influence of spinalization on the effects of NCX-701 was also studied. NCX-701 and paracetamol were equipotent in reducing single motor unit responses to noxious mechanical stimulation, ID50s of 320+/-1.2 and 305+/-1.2 micromol/kg, respectively. The mechanism of action seems to be different since NCX-701, but not paracetamol, reduced wind-up. This effect suggests a central action, probably within the spinal cord. Sham spinalization reduced the effect of NCX-701 on nociceptive responses drastically. In spinalized animals, however, the effect was similar to that observed in intact animals, indicating a strong effect of NCX-701 at spinal sites, which counterbalances the decrease in the activity induced by the surgery. We conclude that NCX-701 is an effective antinociceptive drug in arthritic animals, with a mechanism of action located in the spinal cord, and different to that of paracetamol.

A critical appraisal of COX-2 selective inhibition and analgesia: how good so far?

The development of COX-2 selective inhibitors has opened a new era of clinical investigation in NSAIDs. Discussion of the established concepts of inflammation and therapeutical uses of these drugs has changed the rationale for its clinical use and therapeutic labeling of these drugs. A comprehensive discussion across basic science and clinical areas involved in each of these concepts is presented. This led to a remarkable re-evaluation of our insights on their traditionally proposed mechanisms of analgesia, their side-effects, and the clinical indication of NSAIDs as "over the counter" pain killers. This may shift physicians toward a more rational use of this drug class.