Mechanism of cancer pain

Abstract

Ongoing and breakthrough pain is a primary concern for the cancer patient. Although the etiology of cancer pain remains unclear, animal models of cancer pain have allowed investigators to unravel some of the cancer-induced neuropathologic processes that occur in the region of tumor growth and in the dorsal horn of the spinal cord. Within the cancer microenvironment, cancer and immune cells produce and secrete mediators that activate and sensitize primary afferent nociceptors. Pursuant to these peripheral changes, nociceptive secondary neurons in spinal cord exhibit increased spontaneous activity and enhanced responsiveness to three modes of noxious stimulation: heat, cold, and mechanical stimuli. As our understanding of the peripheral and central mechanisms that underlie cancer pain improves, targeted analgesics for the cancer patient will likely follow.

Figure 1

The key cellular components within the cancer microenvironment include the cancer cells, primary afferent nociceptors, and immune cells (e.g., mast cells). Cells comprising the cancer produce and secrete mediators into the cancer microenvironment that modulate nociception. Such mediators include: protons, ET-1, TNFα, NGF, trypsin, and opioids. The cancer can indirectly increase nociceptive mediators such as bradykinin (BK) or tryptase. BK production is increased by the secretion of kallikrein by the cancer cell. Tryptase is released through stimulation of mast cells by the cancer. Certain mediators, such as ET-1 can activate receptors both on the cancer cell (ET_BR) and the primary afferent nociceptors (ET_AR). The various mediators stimulate the associated receptors on primary afferent nociceptors to produce both nociception and antinociception. (See text for details and references. Blue arrow indicates secretion. Green arrow indicates activation. Red arrow indicates sensitization.)

Figure 2

Cannabinoid receptor (CBr) agonists and antagonists act peripherally in the cancer microenvironment on CBr1 and CBr2 subtypes and have central effects when administered systemically. CBr agonists reduce cancer-induced nociception. In the carcinoma microenvironment, CBr1 receptors are found on the primary afferent nociceptive free nerve endings, whereas CBr2 might be present on the carcinoma cells given that they are found on keratinocytes. Activation of peripheral CBr1 reduces hyperalgesia by opening G protein–coupled inwardly rectifying potassium (GIRK) channels, by inhibiting voltage-dependent calcium channels (VDCC), and by inhibiting release of substance P (SP) and calcitonin gene–related peptide (CGRP). An additional mechanism for reducing cancer-induced nociception, including mechanical allodynia, comes from activation of CBr2 on the carcinoma cell, which potentially leads to secretion of beta-endorphins, as occurs in keratinocytes. The endorphins activate mu opioid receptors on the peripheral nociceptive afferent, which open GIRK channels. WIN 55,212-2 and CP 55,940 are non-selective CBr agonists. AM1241 is a selective CBr2 agonist. Selective antagonists include SR141716A for CBr1 and SR144528 for CBr2. The left-hand side of the figure illustrates additional sites of actions for systemic administration of agonists or antagonists of CBr1, namely the dorsal root ganglion cell body, the dorsal horn presynaptic terminals of the primary afferent neuron, and the brain. (See text for details and references. Blue arrows indicate secretion. Green arrows indicate agonism or activation. Red arrows indicate antagonism; red blunt arrows represent inhibition).