zaprinast and Pain

G-protein coupled receptor 35 (GPR35) is a former "orphan receptor" expressed in brain and activated by either kynurenic acid or zaprinast. While zaprinast has been studied as a phosphodiesterase inhibitor, kynurenic acid (KYNA) is a tryptophan metabolite and has been proposed as the endogenous ligand for this receptor. In the present work, we showed that GPR35 is present in the dorsal root ganglia and in the spinal cord and in order to test the hypothesis that GPR35 activation could cause analgesia, we administered suitable doses of zaprinast or we increased the local concentration of KYNA by administering a precursor (kynurenine) or by inhibiting its disposal from the CNS (with probenecid). We used the "writhing test" induced by acetic acid i.p. injection in mice. KYNA and kynurenine plasma and spinal cord levels were measured with HPLC techniques. Kynurenine (30, 100, 300 mg/kg s.c.) increased plasma and spinal cord levels of KYNA and decreased the number of writhes in a dose dependent manner. Similarly, probenecid was able to increase KYNA levels in plasma and spinal cord, to reduce the number of writes and to amplify kynurenine effects. Furthermore, zaprinast had antinociceptive effects in the writhing test without affecting KYNA levels. In agreement with its affinity for GPR35 receptor (approximately 10 times higher than that of KYNA), zaprinast action occurred at relatively low doses. No additive actions were obtained when kynurenine and zaprinast were administered at maximally active doses. Our results suggest that GPR35 could be an interesting target for innovative pharmacological agents designed to reduce inflammatory pain. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Topics: Analgesics; Animals; Antidepressive Agents, Second-Generation; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Ganglia, Spinal; Gene Expression; Inflammation; Kynurenic Acid; Kynurenine; Male; Mice; Neuroglia; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Probenecid; Purinones; Receptors, G-Protein-Coupled; Spinal Cord; Tryptophan

The cyclic guanosine monophosphate level, which causes an antinociception, is increased in cells as a direct result of phosphodiesterase inhibition. This study used a nociceptive test to examine the nature of the pharmacological interaction between intrathecal zaprinast, a phosphodiesterase inhibitor, and morphine.. Catheters were inserted into the intrathecal space through an incision in the atlantooccipital membrane of male Sprague-Dawley rats. As a nociceptive model, 50 microL of a 5% formalin solution was injected into the hind paw. After observing the effect of zaprinast (37, 111, 369 nmol) and morphine (1, 4, 10, 40 nmol) alone, the interactions of their combination were examined by an isobolographic analysis.. Intrathecal zaprinast (P < 0.05) and morphine (P < 0.05) dose-dependently suppressed the flinching observed during phase 1 and phase 2 in the formalin test. The ED50 values (95% confidence intervals) of zaprinast and morphine in phase 1 were 161.9 (87.9-298.3) and 11.6 nmol (4.8-27.9 nmol), respectively. The phase 2 ED50 values (95% confidence intervals) of zaprinast and morphine were 229.9 (142.5-370.9) and 3.9 nmol (1.9-7.6 nmol), respectively. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery a zaprinast-morphine mixture in both phases. The ED50 values of (95% confidence intervals) zaprinast in the combination of zaprinast with morphine in phase 1 and phase 2 were 14.2 (4.9-40.6) and 10.4 nmol (3-35.9 nmol), respectively.. Intrathecal zaprinast and morphine are effective against acute pain and facilitated pain state. Zaprinast interacts synergistically with morphine.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Synergism; Formaldehyde; Injections, Spinal; Male; Morphine; Muscle Tonus; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Purinones; Rats; Rats, Sprague-Dawley; Reflex

Zaprinast is a phosphodiesterase inhibitor that is active in various models of pain when administered locally. In addition, the antinociception of zaprinast is involved in the nitric oxide (NO)-cGMP pathway. However, the effect of zaprinast administered spinally has not been examined. Therefore, this study examined the effect of zaprinast on the formalin-induced nociception at the spinal level. Next, the role of the NO-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. Catheters were inserted into the intrathecal space of male Sprague-Dawley (SD) rats. Pain was induced by applying 50 microl of a 5% formalin solution to the hindpaw. The change in the zaprinast-induced effect was examined after an intrathecal pretreatment with a NO synthase inhibitor (l-NMMA), a guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide). Zaprinast produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Intrathecal l-NMMA, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase of the formalin test. These results suggest that zaprinast is effective against both acute pain and the facilitated pain state at the spinal level. However, the NO-sensitive cGMP-potassium channel pathway is not contributable to the antinociceptive mechanism of zaprinast in the spinal cord.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Analgesics; Animals; Cyclic GMP; Formaldehyde; Glyburide; Injections, Spinal; Male; Nitric Oxide; omega-N-Methylarginine; Oxadiazoles; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Potassium Channels; Purinones; Quinoxalines; Rats; Rats, Sprague-Dawley; Signal Transduction

In view of the scarce information about the analgesic mechanism of kappa-opioid receptor agonists, the objective of the present study was to determine whether nitric oxide (NO) is involved in the peripheral antinociception of bremazocine, a kappa-opioid receptor agonist. Three drugs all interfering with the L-arginine/NO/cyclic GMP pathway were tested using the rat paw model of carrageenan-induced (250 microg) hyperalgesia: (a) N(G)-nitro-L-arginine (a nonselective NO-synthase inhibitor), (b) methylene blue (a guanylate cyclase inhibitor), and (c) zaprinast (a cyclic GMP phosphodiesterase inhibitor). Intraplantar administration of bremazocine (20, 40 and 50 microg) caused a dose-dependent peripheral antihyperalgesia against carrageenan-induced hyperalgesia. The possibility of the higher dose of bremazocine (50 microg) having central or systemic effect was excluded since administration of the drug into the left paw did not elicit antinociception in the contralateral paw. However, when the dose of bremazocine was increased to 100 microg, a significant increase in the nociceptive threshold was observed, as measured in the hyperalgesic contralateral paw. Peripheral antihyperalgesia induced by bremazocine (50 microg) was significantly reduced in a dose-dependent manner when N(G)-nitro-L-arginine (6, 9, 12 and 25 microg) or methylene blue (250, 375 and 500 microg) was injected before. Previous treatment with 50 microg of zaprinast (which had no effect when administered alone) potentiated the antihyperalgesic effect of bremazocine (20 microg). Our data suggest that bremazocine elicits peripheral antinociception by activation of the L-arginine/NO/cyclic GMP pathway and that nitric oxide is an intermediary in this mechanism, forming cyclic GMP.

Topics: Analgesics; Animals; Arginine; Benzomorphans; Cyclic GMP; Guanylate Cyclase; Hyperalgesia; Male; Methylene Blue; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pain; Phosphodiesterase Inhibitors; Purinones; Rats; Rats, Wistar; Receptors, Opioid, kappa