Laser-photobiomodulation on experimental cancer pain model in Walker Tumor-256

Highlights

• Laser-photobiomodulation has been successfully used in pain control.

• Cancer pain afflicts 20% to 50% of patients with malignant neoplasms.

• Laser irradiation of tumor injected in rat paw reduced pain reflex.

• Laser irradiation reduced COX-2 and Bdkrb1 gene expression.

• Laser irradiation raised IL-10 gene expression.

Abstract

Context

Cancer Pain is considered a common and significant clinical problem in malignant neoplasms, comprising 20% to 50% of all patients with tumor progression. Laser photobiomodulation (L-PBM) has been used in a multitude of pain events, ranging from acute trauma to chronic articular. However, L-PBM has never been tested in cancer pain.

Objectives

Evaluate hyperalgesia, edema, COX-1, COX-2, IL-10, and Bdkrb1 mRNA in low-level laser irradiated Walker-256 tumor-bearing rats.

Methods

Rat hind paw injected with Walker Tumor-256 (W-256) and divided into six groups of 6 rats: G1 (control) - W-256 injected, G2- W-256 + Nimesulide, G3- W-256 + 1 J, G4- W-256 + 3 Jand G5- W256 + 6 J. Laser parameters: λ = 660 nm, 3.57 W/cm², Ø = 0.028 cm². Mechanical hyperalgesia was evaluated by Randall–Selitto test. Plethysmography measured edema; mRNA levels of COX-1, COX-2, IL-10, and Bdkrb1were analyzed.

Results

It was found that the W-256 + 1 J group showed a decrease in paw edema, a significant reduction in pain threshold. Higher levels of IL-10 and lower levels of COX-2 and Bdkrb1 were observed.

Conclusion

Results suggest that 1 J L-PBM reduced the expression of COX-2 and Bdkrb1 and increasing IL-10 gene expression, promoting analgesia to close levels to nimesulide.

Introduction

Cancer pain is considered one of the most common, early, distressing, and primary concerns in malignant neoplasms comprising 20% to 50% of all patients with tumor progression, and more than 50% of these patients experience severe pain and uncontrollable during the disease [1,2,5] In 2014, more than 18 million cases of cancer were reported worldwide, and it is predicted that in 2030 there will be 23 million new cases of cancer, with 50% of these cancers being metastatic. Thus, cancer pain affects approximately 17 million cancer patients worldwide, and its prevalence ranges from 33% in remission patients after curative treatment to 64% in metastatic cancer patients presenting 75–90% moderate to intense pain. Although cancer pain may be presented at any time during the course of the disease, it usually increases during tumor progression in up to 90% of these patients with metastatic cancer or, in an advanced stage, will present significant nociceptive or neuropathic pain or both [[6], [7], [8]] Besides, experienced cancer pain, characterized by the presence of hyperalgesia, allodynia, and spontaneous pain. It's a serious and shocking condition that may contribute to the gradual worsening of the patient's quality of life [1,3,4,5] Approximately 75% to 90% of advanced cancer patients should deal with chronic pain syndromes caused by the ineffectiveness of current treatments and/or tumor progression. Therefore, pain management in patients with cancer becomes a primary challenge, crucial and necessary from the beginning of the disease, during long-term treatments and terminal palliative care [[9], [10], [11], [12]].

Several studies have established that cancer pain can be controlled in most patients on current therapeutic basis following guidelines known as the “analgesic ladder” of the World Health Organization (WHO), in which therapeutic regimen is related by the use of opioids in association with non-steroidal anti-inflammatory drugs. However, they may limit the efficacy of the treatment [[12], [13], [14], [15], [16]].

Oncologic pain is not a single condition but a complex, painful state involving several important hyperalgesia syndromes associated with inflammatory, neuropathic, compressive, and ischemic mechanisms [[17], [18], [19], [20], [21]].

Malignant neoplasms are composed of heterogeneous cell populations that contribute to the functionality of the tumor microenvironment. In addition to tumor cells, which contain oncogenic and tumor suppressor mutations, there are tumor stem cells, pericytes, cancer-associated fibroblasts, tumor stromal progenitor cells, endothelial cells, inflammatory process immuno-regulatory cells (macrophages, neutrophils, and T lymphocytes) and primary afferent sensory terminals. Extensive cell communications among these different cell types and structures are carried out by means of production and secretion of chemical mediators. A multitude of redundant and time-dependent proinflammatory and anti-inflammatory/resolution mediators are detected in tumor environment, like neurotrophins (nerve growth factor (NGF), neutrophil factor-derived brain (BDNF), neurotrophin-3 (NT-3), endothelins, bradykinins, prostaglandins, prostacyclins, thromboxanes (produced by COX-1, COX-2), interleukins (IL-1β, IL-6, IL-10, and TNF-α), chemokines, epidermal growth factor (EGF), transforming growth factor (TGFβ), platelet-derived growth factor (PDGF), protons and proteases. Some of these mediators are able to induce nociception and/or stimulate nociceptor potentials (allodynia or hyperalgesia) while others attenuate nociceptors potential [[22], [23], [24], [25]].

Laser-Photobiomodulation (L-PBM) is a low-intensity light therapy and whose produced effect is achieved mainly by altering the chemical function of a restrict group of biomolecules (chromophores/photoreceptors). Photoreceptors' biochemical changes trigger a cascade of ongoing events that transiently modify cell function [26,27].

Literature supports the view that cytochrome c oxidase (IV-complex of the respiratory chain) is the primary photoreceptor for red/near infra-red lasers. Nitric oxide (NO) produced in cells can inhibit the respiratory chain by occupying the O2 acceptor site in cytochrome c oxidase competing/displacing it. It is proposed that L-PBM can photo-dissociate NO from the O2 acceptor site in cytochrome c oxidase and reverse the mitochondrial NO-inhibition of respiration, enhancing ATP production [26,27].

L-PBM has been used as an anti-inflammatory, anti-edematous, and analgesic therapeutic tool in a wide range of conditions. The analgesic effect has been reported in both chronic and acute conditions. Neuropathic pain conditions can also be treated, such as post-herpetic neuralgia, trigeminal neuralgia, and diabetic neuropathy [[28], [29], [30], [31], [32], [33], [34]].

L-PBM also has been successfully used for prevention and management of chemoradiation therapy side effects in head and neck cancer [[58], [59], [60], [61]] Despite symptom alleviation in mucositis due to cancer treatment, L-PBM was never tested as an analgesic tool in cancer pain itself [35,36].

Based on these considerations, this study evaluated the analgesic, anti-edematous, and anti-inflammatory effects of LLLT on the experimental cancer pain model of Walker Tumor 256 cells [37].