Related Experiment Videos
Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase
1Department of Anesthesiology and Critical Care Medicine, Blalock 1415, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-4965, USA.
Abstract:
To date, the exact role of inducible nitric oxide synthase (iNOS) in inflammatory pain remains controversial. In the present study, we combined a pharmacological strategy (using a selective iNOS inhibitor) with a genomic strategy (using mice lacking the iNOS gene) to address the function of iNOS in the central mechanism of carrageenan-induced persistent inflammatory pain. In the wild type mice, intrathecal administration of L-N(6)-(1-iminoethyl)-lysine, a selective iNOS inhibitor, significantly inhibited thermal hyperalgesia in the late phase but not in the early phase of carrageenan inflammation. Moreover, iNOS mRNA expression in the lumbar enlargement segments of the spinal cord was dramatically induced at 24 h (late phase) after injection of carrageenan into a hind paw. Interestingly, targeted disruption of iNOS gene did not affect carrageenan-induced thermal hyperalgesia in either the early (2-6 h) or late phase. In the lumbar enlargement segments of iNOS knockout mice, nitric oxide synthase (NOS) enzyme activity remained at a similar level to that of the wild type mice at 24 h after carrageenan injection. We found that intrathecal administration of 7-nitroindazole (a selective neuronal NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (a selective endothelial NOS inhibitor), significantly reduced carrageenan-induced thermal hyperalgesia in both the early phase and the late phase in iNOS knockout mice. We also found that expression of neuronal NOS but not endothelial NOS in the lumbar enlargement segments was significantly increased in iNOS knockout mice compared with wild type mice at 24 h after carrageenan injection. Our results indicate that neuronal NOS might compensate for the function of iNOS in the late phase of carrageenan-induced inflammatory pain in iNOS knockout mice. This suggests that iNOS may be sufficient, but not essential, for the late phase of the carrageenan-induced thermal hyperalgesia.
Insights
Inducible nitric oxide synthase (iNOS) is sufficient but not essential for inflammatory pain. Neuronal NOS compensates for iNOS deficiency, suggesting complex pain regulation mechanisms.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- The role of inducible nitric oxide synthase (iNOS) in inflammatory pain is debated.
- Carrageenan-induced inflammatory pain is a common model to study pain mechanisms.
Purpose of the Study:
- To investigate the function of iNOS in the central mechanisms of carrageenan-induced inflammatory pain.
- To differentiate the roles of iNOS and other nitric oxide synthase (NOS) isoforms in pain.
Main Methods:
- Used a combination of pharmacological inhibition (selective iNOS inhibitor) and genetic knockout (iNOS-deficient mice).
- Administered carrageenan to induce inflammatory pain and assessed thermal hyperalgesia.
- Measured iNOS mRNA expression and NOS enzyme activity in spinal cord tissue.
- Utilized selective inhibitors for neuronal NOS and endothelial NOS in iNOS knockout mice.
Main Results:
- Selective iNOS inhibition reduced thermal hyperalgesia in the late phase of carrageenan inflammation in wild-type mice.
- iNOS knockout mice showed no significant difference in thermal hyperalgesia compared to wild-type mice.
- In iNOS knockout mice, neuronal NOS inhibition, but not endothelial NOS inhibition, reduced thermal hyperalgesia.
- Neuronal NOS expression was upregulated in iNOS knockout mice spinal cords.
Conclusions:
- iNOS is sufficient, but not essential, for the late phase of carrageenan-induced inflammatory pain.
- Neuronal NOS may compensate for the absence of iNOS in inflammatory pain.
- This compensation by neuronal NOS highlights the complex interplay of NOS isoforms in pain modulation.