Limits...
Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice.

Guan Y, Yaster M, Raja SN, Tao YX - Mol Pain (2007)

Bottom Line: Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury.The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord.Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 355 Ross, 720 Rutland Ave,, Baltimore, Maryland 21205, USA. ytau@jhmi.edu

ABSTRACT
Neuronal nitric oxide synthase (nNOS) is a key enzyme for nitric oxide production in neuronal tissues and contributes to the spinal central sensitization in inflammatory pain. However, the role of nNOS in neuropathic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to examine the effects of genetic knockout and pharmacologic inhibition of nNOS on neuropathic pain induced by unilateral fifth lumbar spinal nerve injury in mice. In contrast to wildtype mice, nNOS knockout mice failed to display nerve injury-induced mechanical hypersensitivity. Furthermore, either intraperitoneal (100 mg/kg) or intrathecal (30 microg/5 microl) administration of L-NG-nitro-arginine methyl ester, a nonspecific NOS inhibitor, significantly reversed nerve injury-induced mechanical hypersensitivity on day 7 post-nerve injury in wildtype mice. Intrathecal injection of 7-nitroindazole (8.15 microg/5 microl), a selective nNOS inhibitor, also dramatically attenuated nerve injury-induced mechanical hypersensitivity. Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury. The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord. Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.

Show MeSH

Related in: MedlinePlus

Effect of intraperitoneal (i.p.) injection of L-NAME or D-NAME on mechanical pain hypersensitivity on day 7 after L5 spinal nerve injury in WT mice. Paw withdrawal responses to 0.24 mN (A and C) and 4.33 mN (B and D) mechanical stimuli on the ipsilateral (A and B) and contralateral (C and D) sides. *P < 0.05, **P < 0.01 vs the corresponding baseline. ##P < 0.01 vs the post-drug, D-NAME-treated group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2089056&req=5

Figure 2: Effect of intraperitoneal (i.p.) injection of L-NAME or D-NAME on mechanical pain hypersensitivity on day 7 after L5 spinal nerve injury in WT mice. Paw withdrawal responses to 0.24 mN (A and C) and 4.33 mN (B and D) mechanical stimuli on the ipsilateral (A and B) and contralateral (C and D) sides. *P < 0.05, **P < 0.01 vs the corresponding baseline. ##P < 0.01 vs the post-drug, D-NAME-treated group.

Mentions: We examined the effect of systemic inhibition of NOS on nerve injury-induced mechanical pain hypersensitivity in WT mice. A nonspecific NOS inhibitor, L-NG-nitro-arginine methyl ester (L-NAME) and its inactive enantiomer, D-NAME, were administered intraperitoneally on day 7 post-nerve injury. Intraperitoneal injection of D-NAME failed to produce a significant effect on nerve injury-induced increases in ipsilateral paw withdrawal frequencies in response to low- and moderate-intensity mechanical stimuli (n = 9; Fig. 2A, B). However, intraperitoneal injection of L-NAME significantly reversed nerve injury-evoked mechanical hypersensitivity on the ipsilateral side (n = 11; Fig. 2A, B). The average paw withdrawal frequencies to low- and moderate-intensity mechanical stimuli after administration of L-NAME were reduced by 58% and 48%, respectively, compared to the values in the D-NAME-treated groups (P < 0.01). As expected, neither L-NAME nor D-NAME at the doses used affected contralateral paw withdrawal responses to mechanical stimuli (Fig. 2C, D).


Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice.

Guan Y, Yaster M, Raja SN, Tao YX - Mol Pain (2007)

Effect of intraperitoneal (i.p.) injection of L-NAME or D-NAME on mechanical pain hypersensitivity on day 7 after L5 spinal nerve injury in WT mice. Paw withdrawal responses to 0.24 mN (A and C) and 4.33 mN (B and D) mechanical stimuli on the ipsilateral (A and B) and contralateral (C and D) sides. *P < 0.05, **P < 0.01 vs the corresponding baseline. ##P < 0.01 vs the post-drug, D-NAME-treated group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2089056&req=5

Figure 2: Effect of intraperitoneal (i.p.) injection of L-NAME or D-NAME on mechanical pain hypersensitivity on day 7 after L5 spinal nerve injury in WT mice. Paw withdrawal responses to 0.24 mN (A and C) and 4.33 mN (B and D) mechanical stimuli on the ipsilateral (A and B) and contralateral (C and D) sides. *P < 0.05, **P < 0.01 vs the corresponding baseline. ##P < 0.01 vs the post-drug, D-NAME-treated group.
Mentions: We examined the effect of systemic inhibition of NOS on nerve injury-induced mechanical pain hypersensitivity in WT mice. A nonspecific NOS inhibitor, L-NG-nitro-arginine methyl ester (L-NAME) and its inactive enantiomer, D-NAME, were administered intraperitoneally on day 7 post-nerve injury. Intraperitoneal injection of D-NAME failed to produce a significant effect on nerve injury-induced increases in ipsilateral paw withdrawal frequencies in response to low- and moderate-intensity mechanical stimuli (n = 9; Fig. 2A, B). However, intraperitoneal injection of L-NAME significantly reversed nerve injury-evoked mechanical hypersensitivity on the ipsilateral side (n = 11; Fig. 2A, B). The average paw withdrawal frequencies to low- and moderate-intensity mechanical stimuli after administration of L-NAME were reduced by 58% and 48%, respectively, compared to the values in the D-NAME-treated groups (P < 0.01). As expected, neither L-NAME nor D-NAME at the doses used affected contralateral paw withdrawal responses to mechanical stimuli (Fig. 2C, D).

Bottom Line: Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury.The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord.Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 355 Ross, 720 Rutland Ave,, Baltimore, Maryland 21205, USA. ytau@jhmi.edu

ABSTRACT
Neuronal nitric oxide synthase (nNOS) is a key enzyme for nitric oxide production in neuronal tissues and contributes to the spinal central sensitization in inflammatory pain. However, the role of nNOS in neuropathic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to examine the effects of genetic knockout and pharmacologic inhibition of nNOS on neuropathic pain induced by unilateral fifth lumbar spinal nerve injury in mice. In contrast to wildtype mice, nNOS knockout mice failed to display nerve injury-induced mechanical hypersensitivity. Furthermore, either intraperitoneal (100 mg/kg) or intrathecal (30 microg/5 microl) administration of L-NG-nitro-arginine methyl ester, a nonspecific NOS inhibitor, significantly reversed nerve injury-induced mechanical hypersensitivity on day 7 post-nerve injury in wildtype mice. Intrathecal injection of 7-nitroindazole (8.15 microg/5 microl), a selective nNOS inhibitor, also dramatically attenuated nerve injury-induced mechanical hypersensitivity. Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury. The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord. Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.

Show MeSH
Related in: MedlinePlus