The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability.

Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, µ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study. PKA fluorescence redistribution assays in CHO cells individually expressing δ-, µ- or κ-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of ED50 (pCO2 increase)/ED50 (antinociception). The abuse liability of DPI-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DPI-125 for δ-, µ- and κ-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DPI-125 exhibited a high respiratory safety profile, clearly related to its high δ-receptor potency. The ratio of the EC50 potencies for the µ- and δ-receptors was found to be positively correlated with the respiratory safety ratio. DPI-125 has similar potencies for µ- and κ-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DPI-125 is safer and less addictive than traditional µ-agonist analgesics. These findings suggest that the development of δ>µâˆ¼κ opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.

Effects of acute and repeated morphine treatment on κ-opioid receptor protein levels in mesocorticolimbic system.

CONTEXT: Our previous study demonstrated that acute and repeated morphine treatment differentially regulated κ-opioid receptor mRNA levels in the rat mesocorticolimbic system. Here, we further investigated the effects of morphine on protein levels of κ-opioid receptor in this reward-related circuitry. METHODS: Three groups of rats received intraperitoneal injection of saline, acute morphine (8.0 mg/kg) and repeated morphine (8.0 mg/kg, once daily for 5 consecutive days) and the κ-receptor protein expression was examined by Western blot analysis. RESULTS: We found that acute morphine treatment did not affect the κ-receptor protein levels in medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and ventral tegmental area (VTA). However, repeated morphine treatment downregulated the κ-receptor protein levels in mPFC and VTA, while there was no significant change in NAc. CONCLUSIONS: These results, along with those reported previously, suggested that morphine dependence may be associated with regionally specific changes in κ-opioid receptor expression in mesocorticolimbic system.

Intravenous ilaprazole is more potent than oral ilaprazole against gastric lesions in rats.

BACKGROUND AND AIMS: Ilaprazole is a novel proton pump inhibitor that has been marketed as an oral therapy for acid-related diseases in China and Korea. This study aimed to compare the gastroprotective effects of intravenous and enteral ilaprazole in rat models. METHODS: The rats were divided into 7-8 groups receiving vehicle, esomeprazole, and different doses of intravenous and enteral ilaprazole. The rats were then exposed to indomethacin (30 mg/kg, i.g.), or water-immersion stress and gastric lesions were examined. The effects of different treatments on histamine (10 µmol/kg/h)-induced acid secretion were also observed. RESULTS: Intravenous ilaprazole exhibited high antiulcer activity in a dose-dependent manner. Ilaprazole at a dose of 3 mg/kg decreased ulcer number and index to the same extent as 20 mg/kg esomeprazole. Moreover, the potency of intravenous ilaprazole is superior to that of intragastric ilaprazole. In anesthetized rats, the inhibitory effect of intravenous ilaprazole on histamine-induced acid secretion is faster and longer-lasting than that of intraduodenal ilaprazole. CONCLUSION: Intravenous ilaprazole is more potent than oral ilaprazole against indomethacin- or stress-induced gastric lesions, with faster and longer inhibition of acid secretion.

[Establishment and application of a mouse model for drug-induced schizophrenia].

Schizophrenia, described as the worst disease affecting mankind, is a severe and disabling mental disorder. Schizophrenia is characterized by complicated symptoms and still lacks a diagnostic neuropathology, so developing schizophrenia animal models which have quantifiable measures tested in a similar fashion in both humans and animals will play a key role in new therapeutic approaches. According to the symptoms of cognitive impairment and emotional disorder, the N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 was applied to induce schizophrenia-like behavior in mice. Locomotor activity and prepulse inhibition (PPI) were selected as indices and the effect of clozapine was also investigated in this model. The results showed that compared with the normal group, MK-801-treated mice exhibited significantly increased locomotor activity and impaired PPI, and pre-exposure to clozapine could ameliorate the abnormality and make it back to normal level. These findings suggest that the model we established could be a useful tool for antipsychotic drug screening.

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418.

AIM: To investigate possible pharmacological mechanisms underlying the antinociceptive effect of and tolerance to N-methyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (030418), a derivative of thienorphine. METHODS: The binding affinity and efficacy of 030418 were determined using receptor binding and guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) assays in CHO-µ, CHO-κ, CHO-δ, and CHO-ORL1 cell membranes. The analgesic activity of and tolerance to 030418 were evaluated in thermal nociceptive tests in mice. The effects of 030418 on opioid receptors were further investigated using in vivo pharmacological antagonist blockade and in vitro tissue preparations. RESULTS: The compound 030418 displayed high binding affinity to all subtypes of opioid receptors with K(i) values in the nanomolar range. In [(35)S]GTPγS binding assay, the maximal stimulation of 030418 to µ-, κ-, δ-receptors and the ORL1 receptor was 89%, 86%, 67% and 91%, respectively. In hot-plate test, the antinociceptive effect of 030418 was more potent and longer than morphine. The nonselective opioid receptor antagonist naloxone could completely block 030418-induced antinociception, while both the µ-opioid receptor antagonist ß-FNA and the κ-opioid receptor antagonist nor-BNI attenuated 030418-induced antinociception. In contrast, the ORL1 receptor antagonist J-113397 enhanced the antinociceptive effect of 030418. Additionally, chronic treatment with 030418 resulted in a dramatic development of tolerance that could not be effectively prevented by J-113397. In guinea pig ileum preparation, the existing action of 030418 could be removed with difficulty after prolonged washing. CONCLUSION: The compound 030418 is a novel agonist of opioid receptors with high efficiency, long-lasting effect and liability to tolerance, which may be closely correlated with the methyl group at the N(17) position and the high hydrophobicity of the C(7)-thiophene group in its chemical structure.

[Primary investigation on heterodimerization of kappa-opioid receptor and ORL1 receptor].

This study investigates whether kappa-opioid receptor and ORL1 receptor may interact to form a heterodimer. In immunofluorescence and co-immunoprecipitation experiments, differentially epitope-tagged receptors, colocalization and heterodimerization of kappa-opioid receptor and ORL1 receptor were used and examined in primary culturing rat neurons, Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. The results show that fluorescence of both kappa-opioid receptor and ORL1 receptor were overlapping in primary culturing hippocampal and cortical neurons. Similarly in co-expressing CHO or HEK293 cells, HA-KOR and Myc-ORL1 were almost exclusively confined to the membranes, revealing extensive colocalization. When Flag-KOR and Myc-ORL1 were co-expressing in CHO cells, heterodimerization was identified to have the ability to co-immunoprecipitate ORL1-receptors with kappa-opioid receptor and vice versa. In the current study, further evidence was provided for the direct interaction of two subtypes of opioid receptors, kappa-opioid receptor and ORL1-receptor, to form the heterodimerization. The finding represents the novel pharmacological mechanism for modulation of opioid receptor function as well as diversity of G protein-coupled receptors.

Inhibition of endothelin-1 and hypoxia-induced pulmonary pressor responses in the rat by a novel selective endothelin-A receptor antagonist, di-n-butylaminocarbamyl-L-leucyl-D-tryptophanyl-D-4-chloro-Phe.

Pulmonary hypertension is a kind of disease associated with a very high rate of mortality, and there are not many effective drugs for the treatment. Today, endothelin (ET)-1 receptor antagonists were proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin-A receptor (ETA) antagonist for treatment of pulmonary hypertension, di-n-butylaminocarbamyl-L-leucyl-D-tryptophanyl-D-4-chloro-Phe, named GF063, was synthesized at base of selective ETA receptor antagonist BQ485 and selected for the further pharmacological characterization. The preliminary pharmacodynamics of GF063 was evaluated by radioligand receptor binding assay and test of antivasoconstriction effects in vitro and in vivo. The integrative pharmacodynamics was evaluated in hypoxia-induced rat pulmonary hypertension. In vitro, GF063 bound to ETA receptor with 100,000-fold higher affinity than to ETB receptor. GF063 concentration dependently inhibited contraction of isolated rat aortic ring induced by ET-1 and shifted the cumulative concentration-contraction response curve to right with no change in the maximal response. In vivo, GF063 inhibited the increase of mean systemic arterial pressure induced by ET-1 in anesthetized rat. In hypoxia-induced rat pulmonary hypertension model, pretreatment with GF063 (40 mg/kg, s.c.) significantly decreased pulmonary artery pressure and right ventricular hypertrophy, also significantly inhibited the increase of ET-1 level in lung, improved hemodynamics, and alleviated the wall thickness of pulmonary vessels. This study indicated that GF063, as a selective ETA receptor antagonist, could inhibit vasoconstriction effects in vivo and in vitro, could prevent pulmonary hypertension induced by hypoxia, and may have great potential to be developed as a new drug of antipulmonary hypertension.

[Establishment of isolated rabbit airway smooth muscles responsiveness model for the pharmacodynamic study of anti-rhinoviruses drugs].

Human rhinoviruses (HRVs) are the causative pathogens in more than half of viral upper respiratory tract infections. Currently, no antiviral agents that are active against HRVs are available for clinical use. Because only higher primates are susceptible to HRVs, the screening of new drug is most commonly based on the cell line model. In this study, isolated rabbit airway smooth muscles (ASM) tissue model has been established, and the airway responsiveness with different treatment has been examined. Relative to control tissues, the maximal constrictor (Tmax) response to ACh increased significantly 150% in ASM inoculated with HRV, and relaxation to isoproterenol has been attenuated to 63%. And the abnormal responsiveness can be inhibited in presence of pretreatment with several new compounds which have been exhibited effective anti-HRV activity on cell lines. The results demonstrate that the established ASM model will be applied to screening the anti-HRVs drugs.

Wnt1/ß-catenin signaling upregulates spinal VGLUT2 expression to control neuropathic pain in mice.

Vesicular glutamate transporter 2 (VGLUT2)-which uptakes glutamate into presynaptic vesicles-is a fundamental component of the glutamate neurotransmitter system. Although several lines of evidence from genetically modified mice suggest a possible association of VGLUT2 with neuropathic pain, the specific role of VGLUT2 in the spinal cord during neuropathic pain, and its regulatory mechanism remain elusive. In this study, we report that spared nerve injury induced an upregulation of VGLUT2 in the spinal cord, and intrathecal administration of small hairpin RNAs (shRNA) against VGLUT2 before or after surgery attenuated mechanical allodynia, and pathologically-enhanced glutamate release. Meanwhile, nerve injury activated the Wnt1/ß-catenin signaling pathway in a quick-onset and sustained manner, and blocking the Wnt1 signaling with a Wnt1 targeting antibody attenuated neuropathic pain. In naïve mice, administration of a Wnt agonist or Wnt1 increased spinal VGLUT2 protein levels. Moreover, intrathecal administration of the Wnt/ß-catenin inhibitor, XAV939 attenuated mechanical allodynia, and this effect was concurrent with that of VGLUT2 downregulation. Pretreatment with VGLUT2 shRNAs abolished the allodynia induced by the Wnt agonist or Wnt1. These findings reveal a novel mechanism wherein there is Wnt1/ß-catenin-dependent VGLUT2 upregulation in neuropathic pain, thus potentiating the development of new therapeutic strategies in pain management.

Synthesis and evaluation of novel chloropyridazine derivatives as potent human rhinovirus (HRV) capsid-binding inhibitors.

Human rhinovirus (HRV) is the most important etiologic agent causing common colds. No effective anti-HRV agents are currently available. In this paper we describe the synthesis and the evaluation of novel chloropyridazine derivatives (compounds 5a-g) as potent human rhinovirus (HRV) capsid-binding inhibitors. Results showed that compound 5e and 5f exhibited effective anti-HRV activity against HRV-2 and HRV-14. In addition, compound 5e and 5f showed lower cytotoxicity than Pirodavir.

[Effect of spinal glutamate transporter 1 on chronic constriction injury of sciatic nerve and morphine tolerance of rats].

In order to investigate the role of spinal glutamate transporter 1 (GLT-1) in the neuropathic pain and morphine tolerance, rat chronic constriction injury (CCI) of sciatic nerve was performed, and the mechanical allodynia was evaluated by mechanical withdrawal threshold (MWT), the expression of GLT-1 was measured by real-time PCR and Western blotting analysis. The results showed that compared to sham group, the MWT of CCI group had decreased approximately 80%. Administration of morphine alone could develop tolerance rapidly in initial two days, and then had no significant difference with CCI group, the expression of GLT-1 was down-regulated. Ceftriaxone sodium alone could improve mechanical allodynia. Co-administration of ceftriaxone sodium with morphine attenuated morphine tolerance and up-regulated GLT-1 expression, and the MWT remained at high level after 6 days. In conclusion, change of spinal GLT-1 expression and function has close correlation with the development of neuropathic pain and morphine tolerance.

[Structure-activity relationships analysis of thienorphine and its derivatives].

Thienorphine is a chemically-new opioid developed in Beijing Institute of Pharmacology and Toxicology. To elucidate the chemical basis for the unique pharmacological effects of thienorphine, 15 derivatives were synthesized according to combinatorial chemistry and the structure-activity relationships of these compounds were studied. It is demonstrated that thienorphine is a potent long-acting partial agonist. N-Cyclopropylmethyl is responsible for the antagonist effect of thienorphine. More importantly, thiophene at the end of side chain is most likely the pharmacophore accounts for the long-lasting effect of thienorphine. Change of the connection of thiophene and the side chain does not result in changes in the antinociceptive activity.

[Pharmacokinetics of 6beta-naltrexol after single and multiple intramuscular injections in Beagle dogs].

The pharmacokinetics of 6beta-naltrexol (6beta-NOL) following single intramuscular administration and multiple intramuscular injection once per day for seven days was studied in 4 Beagle dogs. Plasma concentration of 6beta-NOL in dogs was analyzed by a combination of high performance liquid chromatography (HPLC) and electrochemical detection with naloxone (NLX) as internal standard. After single intramuscular injection of 0.2 mg x kg(-1) 6beta-NOL, the plasma concentration-time curve of the drug was found to fit to a two compartment model with first-order absorption. The main parameters of single dosing were as follows: t1/2alpha was (0.26 +/- 0.23) h, t1/2beta was (4.77 +/- 1.65) h, C(max) was (81.65 +/- 5.61) ng x mL(-1), t(peak) was (0.27 +/- 0.07) h, CL(s) was (1.20 +/- 0.06) L x kg(-1) x h(-1), V/F(c) was (1.94 +/- 0.15) L x kg(-1), and AUC(0-t) was (166.82 +/- 7.68) ng x h x mL(-1), separately. After multiple intramuscular injection of 0.2 mg x kg(-1) 6beta-NOL once per day for seven days, the plasma concentration-time curve of the drug fitted to a two compartment model with first-order absorption too. The main parameters of the last dosing were as follows: t1/2alpha was (0.19 +/- 0.18) h, t1/2beta was (5.79 +/- 1.50) h, C(max) was (79.82 +/- 10.5) ng x mL(-1), t(peak) was (0.18 +/- 0.08) h, CL(s) was (1.12 +/- 0.07) L x kg(-1) x h(-1), V/F(c) was (2.10 +/- 0.27) L x kg(-1), and AUC(0-t) was (173.23 +/- 9.49) ng x h x mL(-1), separately. The difference of the parameters between the first and the last dosing was not significant, showing that the plasma kinetics of 6beta-naltrexol was not changed after multiple administrations. In the course of multiple administration, the peak and valley concentration of plasma 6beta-naltrexol were (79.03 +/- 10.3) and (1.50 +/- 0.93) ng x mL(-1), respectively. No clear adverse events were noted during this study. These results showed that plasma 6beta-naltrexol fits to a two compartment model with first-order absorption in dog after intramuscular administration and their pharmacokinetic parameters were reported. There was no remarkable change on plasma pharmacokinetics of 6beta-naltrexol after multiple intramuscular administrations.

[Effects of beta-lactam antibiotics on development of tolerance and dependence to morphine].

In order to identify ceftriaxone and its analogs whether has the function of anti-tolerance of morphine and study the dose-effect relation of ceftriaxone in mice, hot plate method to measure pain threshold of mouse and naloxone withdrawal models were carried out and compared with normal saline group. Ceftriaxone and cefotaxime had the effect of anti-tolerance and anti-dependence of morphine notably. And ceftriaxone has the effect of anti-tolerance of morphine in a dose dependent manner.

[Synthesis and antinociceptive activity of seselin derivatives].

Natural product seselin and related derivatives with an angular pyranocoumarin skeleton were synthesized from 8-acetyl-7-hydroxycoumarins by condensation with acetone, reduction, and dehydration successively under mild conditions with total yield of > 50%. Twelve seselin derivatives were tested by the writhing response assay induced by acetic acid at a dose of 40 mg x kg(-1). Seselin (4a) and 4,8,8-trimethyl-9,9-dihydro-pyran[2,3-f] chromene-2,10-dione (2b) showed obviously antinociceptive activity with inhibitory effect of 85% and 50%, respectively, more or quite potent than aspirin in the same assay, suggesting that seselin derivatives could be a novel kind of potential antinociceptive agents.

Selective downregulation of vesicular glutamate transporter2 in ventral posterolateral nucleus of thalamus attenuates neuropathic mechanical allodynia in mice.

Vesicular glutamate transporters (VGLUTs) transport glutamate into synaptic vesicles prior to exocytotic release. The expression pattern of VGLUT2 and studies of genetically modified mice have revealed that VGLUT2 contributes to neuropathic pain. We previously showed that VGLUT2 is upregulated in supraspinal regions including the thalamus in mice following spared nerve injury (SNI), and blocking VGLUTs using the VGLUT inhibitor CSB6B attenuated mechanical allodynia. To further evaluate the role of VGLUT2 in neuropathic pain, in this study, we developed a lentiviral vector expressing small hairpin RNAs (shRNAs) against mouse VGLUT2, which was injected into the ventral posterolateral (VPL) nucleus of the thalamus in the presence or absence of SNI. The administration of VGLUT2 shRNAs result in downregulation of VGLUT2 mRNA and protein expression, and decreased extracellular glutamate release in primary cultured neurons. We also showed that VGLUT2 shRNAs attenuated SNI-induced mechanical allodynia, in accordance with knockdown of VGLUT2 in the VPL nucleus in mice. Accordingly, our study supports the essential role of supraspinal VGLUT2 in neuropathic pain in adult mice and, thereby, validates VGLUT2 as a potential target for neuropathic pain therapy.

Changes in VGLUT1 and VGLUT2 expression in rat dorsal root ganglia and spinal cord following spared nerve injury.

Disturbance of glutamate homeostasis is a well-characterized mechanism of neuropathic pain. Vesicular glutamate transporters (VGLUTs) determine glutamate accumulation in synaptic vesicles and their roles in neuropathic pain have been suggested by gene-knockout studies. Here, we investigated the spatio-temporal changes in VGLUT expression during the development of neuropathic pain in wild-type rats. Spared nerve injury (SNI) induced mechanical allodynia from postoperative day 1 to at least day 14. Expression of VGLUT1 and VGLUT2 in dorsal root ganglia and spinal cord was examined by western blot analyses on different postoperative days. We observed that VGLUT2 were selectively upregulated in crude vesicle fractions from the ipsilateral lumbar enlargement on postoperative days 7 and 14, while VGLUT1 was transiently downregulated in ipsilateral DRG (day 4) and contralateral lumbar enlargement (day 1). Upregulation of VGLUT2 was not accompanied by alterations in vesicular expression of synaptotagmin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Thus, VGLUTs expression, especially VGLUT2, is regulated following peripheral nerve injury. Temporal regulation of VGLUT2 expression in spinal cord may represent a novel presynaptic mechanism contributing to injury-induced glutamate imbalance and associated neuropathic pain.

Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate.

Thienorphine (TNP) is a novel partial opioid agonist that has completed phase II clinical evaluation as a promising drug candidate for the treatment of opioid dependence. Previous studies have shown that TNP and its glucuronide conjugate (TNP-G) undergo significant bile excretion. The purpose of this study was to investigate the roles of efflux transporters in regulating biliary excretion and plasma exposure of TNP and TNP-G. An ATPase assay suggested that TNP and TNP-G were substrates of P-gp and MRP2, respectively. The in vitro data from rat hepatocytes showed that bile excretion of TNP and TNP-G was regulated by the P-gp and MRP2 modulators. The accumulation of TNP and TNP-G in HepG2 cells significantly increased by the treatment of mdr1a or MRP2 siRNA for P-gp or MRP2 modulation. In intact rats, the bile excretion, and pharmacokinetic profiles of TNP and TNP-G were remarkably changed with tariquidar and probenecid pretreatment, respectively. Tariquidar increased the Cmax and AUC0-t and decreased MRT and T1/2 of TNP, whereas probenecid decreased the plasma exposure of TNP-G and increased its T1/2. Knockdown P-gp and MRP2 function using siRNA significantly increased the plasma exposure of TNP and TNP-G and reduced their mean retention time in mice. These results indicated the important roles of P-gp and MRP2 in hepatobiliary excretion and plasma exposure of TNP and TNP-G. Inhibition of the efflux transporters may affect the pharmacokinetics of TNP and result in a drug-drug interaction between TNP and the concomitant transporter inhibitor or inducer in clinic.

[Neurogenesis: a novel strategy for the treatment of depression].

It is now generally accepted that the birth of new neurons occurs in brain areas such as hippocampus throughout the lifespan. The waning and waxing of neurogenesis in hippocampus is proposed as a key factor in the decent into and recovery from depression. If hippocampal neurogenesis was blocked, antidepressant would lose its behavioral effects in behavioral models of depression. Long-term, but not short-term, treatment with different classes of antidepressant could stimulate neurogenesis in the hippocampus remarkably. As the regulation of adult neurogenesis continues to be identified, it will provide novel avenues of studying the mechanism and developing pharmacological agents for depressive disorder.

Antinociceptive effects of incarvillateine, a monoterpene alkaloid from Incarvillea sinensis, and possible involvement of the adenosine system.

Incarvillea sinensis is a Bignoniaceae plant used to treat rheumatism and relieve pain in traditional Chinese medicine. As a major component of I. sinensis, incarvillateine has shown analgesic activity in mice formalin tests. Using a series of animal models, this study further evaluated the effects of incarvillateine against acute, inflammatory, and neuropathic pain. Incarvillateine (10 or 20 mg/kg, i.p.) dose-dependently attenuated acetic acid-induced writhing, but did not affect thermal threshold in the hot plate test. In a Complete Freund's Adjuvant model, incarvillateine inhibited both thermal hyperalgesia and paw edema, and increased interleukin-1ß levels. Additionally, incarvillateine attenuated mechanical allodynia induced by spared nerve injury or paclitaxel, whereas normal mechanical sensation was not affected. Incarvillateine did not affect locomotor activity and time on the rotarod at analgesic doses, and no tolerance was observed after 7 consecutive daily doses. Moreover, incarvillateine-induced antinociception was attenuated by theophylline, 1,3-dipropyl-8-cyclopentylxanthine, and 3,7-dimethyl-1-propargylxanthine, but not naloxone, indicating that the effects of incarvillateine on chronic pain were related to the adenosine system, but not opioid system. These results indicate that incarvillateine is a novel analgesic compound that is effective against inflammatory and neuropathic pain, and that its effects are associated with activation of the adenosine system.