8-bromocyclic-gmp and Pain

The mechanisms that underlie the development of vincristine-induced painful neuropathy are poorly understood. The nitric oxide (NO)-cGMP pathway has been reported to be involved in the spinal transmission of nociceptive information. In the present study, we examined whether alterations in spinal nociceptive processing via the NO-cGMP pathway contribute to vincristine-induced painful neuropathy in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg 1 day after the measurement of pre-drug latency in the tail-flick test, and then treated with a dose of 0.125 mg/kg twice a week for 6 weeks. In vincristine-treated mice, a significant decrease in tail-flick latencies developed at 4 weeks after treatment. Pretreatment with L-arginine (30-300 mg/kg, s.c.), a substrate of NO synthase (NOS), dose-dependently increased the tail-flick latencies in vincristine-treated mice. The L-arginine-induced increase in tail-flick latencies in vincristine-treated mice was completely reversed by i.t. pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 3-30 nmol), a NOS inhibitor. Furthermore, i.t. pretreatment with 8-bromoguanosine 3', 5'-cyclic monophosphate (8-Br-cGMP, 0.3-3.0 nmol), a membrane-permeable cGMP analog, dose-dependently increased the tail-flick latencies in vincristine-treated mice. The contents of NO metabolites, cGMP and protein levels of neuronal NOS in the spinal cord in vincristine-treated mice were significantly reduced compared to those in vehicle-treated naive mice. These results indicate that dysfunction of the L-arginine/NO/cGMP cascade in the spinal cord may trigger vincristine-induced thermal hyperalgesia in mice.

Topics: Analysis of Variance; Animals; Arginine; Blotting, Western; Cyclic GMP; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Injections, Spinal; Male; Mice; Mice, Inbred ICR; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxadiazoles; Pain; Pain Measurement; Quinoxalines; Reaction Time; Spinal Cord; Time Factors; Vincristine

Caffeine potentiation of ketorolac-induced antinociception in the pain-induced functional impairment model in rats was assessed. Caffeine alone was ineffective, but increased the effect of ketorolac without affecting its pharmacokinetics. Intra-articular administration of adenosine and N6-cyclohexyladenosine (CHA, an adenosine A1 receptor agonist), but not 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680, an adenosine A2A receptor agonist), significantly increased ketorolac antinociception. This effect was not local, as contralateral administration was also effective. Ipsilateral and contralateral administration of adenosine and CHA also increased antinociception by ketorolac-caffeine. Intra-articular 8-Bromo-adenosine cyclic 3',5'-hydrogen phosphate sodium or 8-Bromo-guanosine-3',5'-cyclophosphate sodium (cGMP) given ipsilaterally or contralaterally did not affect ketorolac-induced antinociception. Nevertheless, ipsilateral, but not contralateral, administration of 8-Br-cGMP significantly increased antinociception by ketorolac-caffeine, suggesting a local effect. The results suggest that caffeine potentiation of ketorolac antinociception is mediated, at least partially, by a local increase in cGMP and rule out the participation of adenosine receptor blockade.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Administration, Topical; Analgesics, Non-Narcotic; Animals; Caffeine; Central Nervous System Stimulants; Cyclic GMP; Cyclohexylamines; Disease Models, Animal; Drug Synergism; Female; Ketorolac; Pain; Pain Measurement; Purinergic P1 Receptor Agonists; Rats; Rats, Wistar; Time Factors