nitroarginine and Neuralgia

This study has investigated whether the galactosyl ester prodrug of N(ω)-nitro-L-arginine (NAGAL), shows enhanced analgesic efficacy in healthy mice and in models of visceral and neuropathic pain: the writhing test and the spared nerve injury (SNI), respectively. NAGAL was compared to methyl ester pro-drug of N(ω)-nitro-l-arginine (L-NAME), a widely exploited non-specific nitric oxide synthase (NOS) inhibitor, for analgesic potential. The writhing test revealed that the ED(50) value, along with the 95% confidence limit (CL) was 3.82 (1.77-6.04) mg/kg for NAGAL and, 36.75 (20.07-68.37) mg/kg for L-NAME. Notably, NAGAL elicited a greater anti-allodynic effect than L-NAME did in neuropathic mice. Biomolecular and morphological studies revealed that spared nerve injury increased the expressions of pro-inflammatory enzymes (caspase-1) and two glial cell biomarkers: integrin alpha M (ITGAM) and glial fibrillary acidic protein (GFAP) in the spinal cord. Finally, GLUT-3, an isoform of the hexose transporters capable to bind NAGAL and inducible NOS (iNOS), were found to be over-expressed in the activated astrocytes of the spinal cord of neuropathic mice. NAGAL administration normalized expression levels of these biomarkers. NAGAL showed a greater efficacy in inhibiting visceral pain and allodynia than L-NAME possibly by a greater cell permeation through the hexose transporter which is highly over-expressed by activated glia.

Topics: Analgesics; Animals; Astrocytes; Blood Pressure; Caspases; Galactose; Gene Expression Regulation, Enzymologic; Glucose Transporter Type 3; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Microglia; Neuralgia; Neuroglia; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type II; Nitroarginine; Prodrugs; Psychomotor Performance; RNA, Messenger; Sciatic Nerve; Time Factors

The aim of this investigation was to assess the role that NO plays in the antinociceptive activity of tramadol using a rat model of neuropathic pain. Thirty male Wistar rats weighing 200-250 g were randomly divided into five equal groups. The neuropathic pain model used for the study was chronic constrictive injury (CCI) model. Three weeks after the surgical procedure, each rat was tested to assess mechanical threshold in grams using an electronic algometer. After CCI was induced, tramadol hydrochloride was administered by intraperitoneal (i.p.) injection in all groups, and Nomega-nitro-L-arginine (L-NA) and L-arginine were administered i.p. or intrathecally (i.t.) depending on the group. Tramadol was administered in 10 mg/kg doses i.p., L-NA was given in 10 mg/kg doses i.p. and in 30 microg/kg doses i.t.. L-arginine was given in 10 mg/kg doses i. p. and in 50 microg/kg doses i.t.. The multiple agents were given 30 minutes apart from each administration. Intraperitoneal administration of tramadol (Group 1) only increased mechanical threshold in the rats' left hind paw, whereas in i.p. L-NA group (10 mg/kg) (Group 2) produced a significant reduction of the mean mechanical antinociceptive threshold (p<0.05). Like this, in i.t. L-NA group (30 microg/kg) (Group 4) a significant reduction of the mean mechanical antinociceptive threshold (p<0.05) was also observed. The mean threshold values in Group 2 (i.p. tramadol+i.p. L-NA) and Group 4 (i.p. tramadol+i.t. L-NA) were not significantly different. The mean threshold values in Groups 3 (i.p. tramadol+i.p. L-NA+i.p. L-arginine) and 5 (i.p. tramadol+i.t. L-NA+i.t. L-arginine) were also similar. The mean mechanical antinociceptive threshold was significantly increased in Group 3 (i.p. L-NA+L-arginine) and Group 5 (i.t. L-NA+L-arginine) when compared to Group 1 (i.p. tramadol only) (p<0.05 for both). The results of this study support the involvement of the L-arginine/nitric oxide pathway in the antinociceptive effect of tramadol in a rat model of neuropathic pain.

Topics: Analgesics; Animals; Arginine; Disease Models, Animal; Injections, Intraperitoneal; Male; Nerve Compression Syndromes; Neuralgia; Nitric Oxide; Nitric Oxide Donors; Nitroarginine; Nociceptors; Rats; Rats, Wistar; Tramadol

Low intrathecal (i.t.) doses of the nitric oxide (NO)-donor 3-morpholinosydnonimine (SIN-1) (0.1-2.0 microg/10 microl) reduced, while higher doses had no effect (5 or 100 microg/10 microl) or increased (10 and 20 microg/10 microl) the mechanical allodynia induced by chronic ligature of the sciatic nerve in rats. SIN-1 (0.1-100 microg/10 microl; i.t.) produced only antinociceptive effect in the rat tail flick test. The inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (4 microg/10 microl; i.t.), abolished the antinociceptive effects of SIN-1 in both tests and reduced the effect of high doses of SIN-1 in neuropathic rats. Hemoglobin (100 microg/10 microl; i.t.), a NO scavenger, inhibited the effect of low dose of SIN-1 and reduced the effect of high dose of SIN-1 in neuropathic rats. 8-Bromo-cGMP (125-500 microg/10 microl; i.t.), reduced the mechanical allodynia in neuropathic rats. The NO-synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (75-300 microg/10 microl; i.t.) reduced the mechanical allodynia evoked by nerve injury and increased the tail-flick latency, respectively. These effects were reduced and inhibited, respectively, by previous i.t. ODQ. The effect of L-NOARG was enhanced in a non-significant manner by hemoglobin. These results indicate that SIN-1 and NO-synthase inhibitors reduce pain through a spinal mechanism that involves activation of guanylate cyclase. The effects of SIN-1 vary depending on the dose and pain model utilized, but its most sensitive effect seems to be antinociception. However, high doses of the NO-donor can intensify ongoing pain.

Topics: Animals; Chronic Disease; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hemoglobins; Injections, Spinal; Ligation; Male; Molsidomine; Nerve Compression Syndromes; Neuralgia; Nitric Oxide; Nitric Oxide Donors; Nitroarginine; Nociceptors; omega-N-Methylarginine; Oxadiazoles; Pain Measurement; Quinoxalines; Rats; Rats, Wistar; Sciatic Nerve