Keywords
1. Nitric Oxide and Inflammatory Pain
2. Cobalt Protoporphyrin IX (CoPP)
3. Tricarbonyldichlororuthenium (II) Dimer (CORM-2)
4. Locus Coeruleus and Neuropathic Pain
5. Heme Oxygenase 1 (HO-1) Inducers
In a groundbreaking study recently published in the International Journal of Molecular Sciences, researchers have unraveled promising therapeutic pathways in managing inflammatory pain—a condition that affects a significant part of the global population. The study, titled “The Effects of Cobalt Protoporphyrin IX and Tricarbonyldichlororuthenium (II) Dimer Treatments and Its Interaction with Nitric Oxide in the Locus Coeruleus of Mice with Peripheral Inflammation,” led by Patricia Moreno and her colleagues from various esteemed institutions, showcases a novel approach in halting the cascade of events in the central nervous system that perpetuates inflammatory pain.
DOI: 10.3390/ijms20092211
In the published work, the research team meticulously explores the biological roles of Heme Oxygenase 1 (HO-1) and carbon monoxide in synchrony with the complex molecular mediator, nitric oxide, apprehending their collective influence in the locus coeruleus (LC)—a cranium nerve structure implicated in pain perception. The study stipulates the two initial components, alongside their newly discovered interplay with nitric oxide, as a prospective remedy against neuropathic and inflammatory ache elicited by peripheral inflammation.
The LC, a critical brain structure that controls alertness and responses to stress and pain, has garnered attention for its relationship with pain modulation. The researchers delved into this region of the brain to scrutinize the antinociceptive (pain-relieving) functions of Cobalt Protoporphyrin IX (CoPP), an inducer of HO-1, and the impacts of both CoPP and Tricarbonyldichlororuthenium (II) Dimer (CORM-2), which liberates carbon monoxide.
Utilizing mice models with inflammatory pain induced by a compound known as Complete Freund’s Adjuvant (CFA), Moreno and her team conducted an assay across multiple genotypes of mice, including wild-type (WT), as well as neuronal (NOS1-KO) and inducible (NOS2-KO) nitric oxide synthase knockout strains. Their results indicate that CoPP effectively attenuated inflammatory pain in a time-dependent manner across the genotypes. Notably, peripheral swelling inflamed astroglia—a type of glial cell in the central nervous system—in the LC of all studied genotypes.
Furthermore, the team unveiled that both CoPP and CORM-2 treatments augmented HO-1 expression and stifled astroglial inception. More crucially, the duality of these treatments preemptively halted the overexpression of NOS1 and rectified the rampant activation of another protein named phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2)—indicative of ERK 1/2 activation—in the WT mice.
Adding another layer to this interlacing biological network, Moreno and her collaborators demonstrate the dynamic interaction between HO-1 and the nitric oxide synthases (NOS1/NOS2) pathways during peripheral inflammation bouts. Their in-depth exploration elucidates the promising potential of CoPP and CORM-2 in bolstering HO-1 expression, thereby moderating the inflammatory response and the ensuing alterations in plasticity spurred by peripheral inflammation within the LC.
The results of this exploration—the fruit of a collaborative effort funded by various international bodies, including the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, and Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, and others from Brazil—render a hopeful prospect in chronic pain management strategies.
This study’s findings offer an enticing precursor for human clinical trials and the potential development of novel painkillers that hold the promise of subduing overzealous astroglial activation and the exacerbated production of nitric oxide—hallmarks of enduring pain conditions. It underscores a prospective treatment paradigm that contravenes the traditional methods, typically saddled with adverse side-effects or habit-forming tendencies.
Delving into the previously published literature reveals a mosaic of evidence reinforcing the significant role of the HO-1/carbon monoxide pathway in mitigating both acute and chronic pain manifestations. Carvalho et al. (2011), Hervera et al. (2012), and Bijjem et al. (2013) pioneered the studies that elucidate how carbon monoxide can dial back neuropathic pain and spinal microglial activation through the inhibition of nitric oxide synthesis in rodent models, painting a picture of the underlying molecular ballet.
Additionally, research by Castany et al. (2016) and Takagi et al. (2009) accentuate the anti-nociceptive framework supported by the carbon monoxide axis, with the latter specifically highlighting the dampening effect of inhaled carbon monoxide on articular expressions of interleukin-1β and monocyte chemoattractant protein-1 in a murine model for arthritis.
The unwoven complexity that surrounds the interconnectedness of HO-1 and various molecular actors, such as nitric oxide synthases and signaling proteins like p-ERK 1/2, is still a fertile ground for continued inquiries. The inception of HO-1, noted for its protective effects against oxidative stress and inflammation, seems to harmonize the intricate crosstalk of these molecules in the neuroinflammatory landscape that accompanies chronic pain.
References
1. Carvalho P.G., Branco L.G., Panissi C.R. (2011). Involvement of the heme oxygenase-carbon monoxide-cGMP pathway in the nociception induced by acute painful stimulus in rats. Brain Res., 1385, 107–113. doi: 10.1016/j.brainres.2011.02.044.
2. Hervera A., Leánez S., Negrete R., Motterlini R., Pol O. (2012). Carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice. PLoS ONE, 7, e43693. doi: 10.1371/journal.pone.0043693.
3. Bijjem K.R., Padi S.S., Lal Sharma P. (2013). Pharmacological activation of heme oxygenase (HO)-1/carbon monoxide pathway prevents the development of peripheral neuropathic pain in Wistar rats. Naunyn Schmiedebergs Arch. Pharmacol., 386, 79–90. doi: 10.1007/s00210-012-0816-1.
4. Castany S., Carcolé M., Leánez S., Pol O. (2016). The role of carbon monoxide on the anti-nociceptive effects and expression of cannabinoid 2 receptors during painful diabetic neuropathy in mice. Psychopharmacology, 233, 2209–2219. doi: 10.1007/s00213-016-4271-4.
5. Takagi T., Naito Y., Inoue M., Akagiri S., Mizushima K., Handa O., Kokura S., Ichikawa H., Yoshikawa T. (2009). Inhalation of carbon monoxide ameliorates collagen-induced arthritis in mice and regulates the articular expression of IL-1β and MCP-1. Inflammation, 32, 83–88. doi: 10.1007/s10753-009-9106-6.
In conclusion, the uncovering of a novel therapeutic avenue intertwining HO-1, carbon monoxide, and nitric oxide in the facet of inflammatory pain heralds a new horizon in pain management therapies. With the promising results from Moreno and the team’s valuable research, the way is paved for futuristic medicine that could alleviate suffering for millions tormented by chronic pain.