The neurobiology of cancer pain

Abstract

The global burden of cancer pain is enormous and opioids, despite their side effects, remain the primary therapeutic approach. The cause of cancer pain is unknown. Mechanisms driving cancer pain differ from those mechanisms responsible for inflammatory and neuropathic pain. The prevailing hypothesis put forward to explain cancer pain posits that cancers generate and secrete mediators which sensitize and activate primary afferent nociceptors in the cancer microenvironment. Moreover, cancers induce neurochemical reorganization of the spinal cord, which contributes to spontaneous activity and enhanced responsiveness. The purpose of this review, which covers clinical and preclinical studies, is to highlight those peripheral and central mechanisms responsible for cancer pain. The challenges facing neuroscientists and clinicians studying and ultimately treating cancer pain are discussed.

Keywords: cancer; cancer pain; pain; sensory system; tumor.

Figure 1

Cancer pain can depend on the histologic type and the anatomic site involved. The patient pictured on the left has a lower lip squamous cell carcinoma. Despite significant pain he delayed his treatment. Ultimately, he sought treatment given his incapacity to eat, drink, or talk secondary to function-induced pain. On the right is an axial CT scan of a 52-year-old woman diagnosed with squamous cell carcinoma of the lung. Her initial complaint was pain in the jaw that turned out to be a metastasis of the lung cancer to her jaw. She had no pain in the lung.

Figure 2

The prevalence of pain based on the histologic type of cancer. The prevalence of pain is greater than 50% for all types of cancer (van den Beuken-van Everdingen and others, 2007).

Figure 3

A model of the cancer microenvironment and possible mechanisms that generate cancer pain. The primary hypothesis underlying cancer pain is that the cancer produces and secretes mediators that sensitize and/or activates primary afferent neurons within the microenvironment. Other constituent cells, which can be recruited by chemoattractants or mediators released by the cancer, including lymphocytes, mast cells, macrophages and fibroblasts also secrete mediators which modulate cancer pain. For example, in prostate cancer fibroblasts are responsible for secreting NGF. Mechanical stimulation of endothelial cells induces the release of ATP; this effect is sensitized by ET-1 (Joseph and others, 2013). Opioids can be secreted into the cancer microenvironment by the cancer or other cells including lymphocytes. BDNF = brain derived neurotrophic factor; BK = bradykinin; BK-R = bradykinin receptor; ET-1 = endothelin-1; ET_AR = endothelin A receptor; ET_BR = endothelin B receptor; GDNF = glial derived neurotrophic factor; NGF = nerve growth factor; PAR2 = protease activated receptor 2; TrkA = tyrosine kinase receptor A; TrkB = tyrosine kinase receptor B; TRPV1 = transient receptor potential vanilloid 1.

Figure 4

Angiogenesis and neurogenesis in the cancer microenvironment are linked processes that contribute to cancer pain. Newly forming blood vessels and nerves interact on a molecular and anatomic basis. VEGF and NGF share common signal transduction pathways. NGF, which induces both angiogenesis and neurogenesis, is secreted by cancers or cancer-associated cells (Nico and others, 2008). Endothelial cells express the NGF receptors, p75 and TrkA receptor, as well as the receptor for VEGF, VEGFR2. SP and CGRP act on their respective receptors, NK1 and CGRPR, on blood vessels to induce endothelial cell proliferation and blood vessel formation. NGF acts through TrkA to generate sensory and sympathetic nerve fibers that innervate the cancer microenvironment; both fiber types contribute to cancer pain. CGRP = calcitonin gene–related protein; CGRPR = calcitonin gene related protein receptor; NGF, nerve growth factor; NK1 = neurokinin-1 receptor; SP = substance P; TH = tyrosine hydroxylase; TrkA = tyrosine kinase receptor A; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.

Figure 5

The incidence of perineural invasion based on the anatomic location of cancer (Bapat and others, 2011).

Figure 6

Cancer induces spinal cord changes. Cancer leads to dorsal horn plasticity which includes up-regulation of pain-related mediators, up-regulation of pain-related receptors, glial and microglial activation, and electrophysiologic changes (i.e., greater amplitude of induced inward currents, evoked discharges, increased response of nociceptive neurons to heat and mechanical stimuli). The up-regulated nociceptive-related mediators are depicted in the orange oval. Cancer decreases AEA signaling through up-regulation of FAAH. The depicted changes are based on work from multiple cancer pain models. Please see the text for details and references. AEA = anandamide; CBr1= cannabinoid receptor 1; CCR2 = chemokine C-C motif receptor 2; DAAO = D-Amino acid oxidase; DYN = dynorphin; EphB1 = ephrin B ligand receptor; FAAH = fatty acid amide hydrolase; GFAP = glial fibrillary acidic protein; HMGB1 = high-mobility group protein 1; JNK = c-jun N-terminal kinase; MCP-1 = monocyte chemoattractant protein-1; NR2B = NMDA (N-methyl-D-aspartate) receptor subunit; TDAG8 = T-cell death-associated gene 8; TNF = tumor necrosis factor; TNFR = tumor necrosis factor receptor; TRPV1 = transient receptor potential vanilloid 1.