Cholawat Pacharinsak and Alvin J. Beitz
The life expectancy for cancer patients has increased dramatically due to knowledge gained from translational research and techno-logical developments in cancer detection and therapy. However, the increase in life expectancy resulting from these technological breakthroughs has raised important issues related to quality of life, in that cancer patients may experience pain for a much longer period of time. Among human patients, 6.6 million people die from cancer each year, and pain can occur at any time during cancer devel-opment and progression (IASP, 2009). The treatment of human patients with cancer pain is typically suboptimal (Fine et al., 2004), because available therapeutics are often aimed at symptom manage-ment rather than targeting the multiple mechanisms underlying the generation and propagation of cancer-associated pain. The present review is focused on neurobiological mechanisms of cancer pain.
PREVALENCE OF CANCER PAIN
The prevalence of cancer pain is difficult to estimate due to a lack of validated methods to effectively assess pain, the variability in the pain experience that occurs among cancer patients, genetic covariants of pain severity, such as those associated with cytokine gene polymorphisms (Reyes-Gibby et al., 2009), and factors asso-ciated with clinician intention to address diverse aspects of pain (Shugarman et al., 2010). While it is difficult to gauge the exact prevalence of cancer pain in human patients, it is more challenging in veterinary medicine. A 1998 study based on postmortem exami-nation, reported that 47% of dogs and 32% of cats died from cancer (Morris Animal Foundation, 1998). These data are consistent with a study of 2002 dogs, which reported that cancer accounted for 20%
and 40–45% of the deaths for 5-year-old and 10- to 16-year-old dogs, respectively (Bronson, 1982). In a recent extensive survey of purebred dogs, it was established that the most common cause of death was cancer (27%) (Adams et al., 2010). The survey also found that cancers of the mammary glands, testicles, gastrointesti-nal tract, lungs, and soft tissue sarcomas are the most common neoplasms of older dogs. Cancer is also a major cause of death in cats and a 2010 survey of juvenile cats in the United Kingdom revealed that 70% of feline neoplasms were malignant or poten-tially would become malignant. The same study reported that the most common tumors in cats were lymphoma (22%) and soft tissue sarcomas (15%) (Schmidt et al., 2010b).
Collectively, these data support the concept that cancer is a major cause of death in cats and dogs, and one would anticipate that cancer, and the subsequent treatments, might have a dramatic impact on their quality of life. Unfortunately, there are no reliable data on the number of animals that suffer from cancer pain. It is likely that many animals are undertreated for cancer-associated pain due to a lack of recognition of pain and suffering, and the lack of baseline and follow-up assessments.
CAUSES OF CANCER PAIN
In human patients, tumor metastasis is the most common cause of pain associated with cancer (Coleman, 2000; 2001; 2006; Jimenez-Andrade et al., 2011). Veterinary cancer patients with advanced disease, particularly those with bone metastasis, also appear to experience significant pain, and it appears that the pain intensity is related to the degree of bone destruction. Cancer patients experience both persistent pain and breakthrough pain and the latter represents a distinct clinical entity (Caraceni & Portenoy, 1999; Caraceni &
Weinstein, 2001). Pain can also be associated with cancer invasion of adjacent tissues, particularly peripheral nerves, adverse affects of treatment (e.g., radiation burns), and concurrent disease (e.g., osteoarthritis) (Caraceni & Weinstein, 2001; Fox, 2010).
MECHANISMS OF CANCER PAIN
While there have been attempts to develop a more comprehen-sive understanding of the underlying mechanisms of cancer pain over the past decade, the cancer pain process has proved to be multifaceted, uncovering the biochemical details has been chal-lenging, and providing a simplistic neurobiological explanation seems unlikely. Cancer pain is a dynamic, complicated process and involves significant plasticity in both the peripheral and central ner-vous systems (Gordon-Williams & Dickenson, 2007). A number of different mediators, including endothelin-1 (ET-1), bradykinin, and calcitonin gene-related peptide (CGRP) are released peripherally and cause various physiological changes in the spinal cord during the course of cancer development. In addition, cancer can induce different types of pain depending upon the type and location of pri-mary and secondary (metastasized) cancer (Schmidt et al., 2010a).
Therefore, the pain caused by cancer can be classified into two
Pain Management in Veterinary Practice, First Edition. Edited by Christine M. Egger, Lydia Love and Tom Doherty.
C2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.
29
30 Section 1 / Introduction and Anatomy, Physiology, and Pathophysiology of Pain categories—cancer-related pain and cancer-unrelated pain.
Cancer-related pain can be classified into cancer-induced pain, pain due to cancer invasion or metastasis, cancer-induced peripheral neuropa-thy, chemotherapy- and radiotherapy-related peripheral neuropaneuropa-thy, and pain due to surgery. Cancer-unrelated pain can be classified into pain due to infection and inflammation, concurrent disorders, and psychological pain.
MECHANISMS OF CANCER-RELATED PAIN
Developing more effective treatments for tumor-induced pain requires a better knowledge of the mechanisms responsible for generating this type of nociception. In the past two decades, a num-ber of animal models have been developed to study many types of complicated pain syndromes, for example, inflammatory pain, neu-ropathic pain, and cancer pain (Ma, 2007). Rodents are the most commonly used animal models of cancer pain. The first animal model of cancer pain was developed in 1998 (Wacnik et al., 1998).
Additional animal models of cancer pain have since been devel-oped in mice (Wacnik et al., 2000), rats (Medhurst et al., 2002;
Pacharinsak & Beitz, 2008), and dogs (Brown et al., 2005).
While our knowledge is far from complete, the complexity of the biological events and mediators that trigger cancer pain are starting to be understood (Table 3.1; Figure 3.1). In the following sections, we will first summarize current knowledge related to peripheral mechanisms of cancer pain, and then provide an overview of the central mechanisms, particularly at the level of the spinal cord, that contribute to this chronic pain state.
Peripheral Mechanisms of Cancer Pain
Several peripheral mechanisms for the generation of cancer pain have been suggested, including ectopic impulse generation (Yaari &
Devor, 1985), spontaneous discharge and decreased noxious stim-ulation threshold (Xiao & Bennett, 2008), and nociceptor sensiti-zation (Hamamoto et al., 2008). Implantation of fibrosarcoma cells into rodent calcaneus bone results in the development of pain-related behaviors and mechanical hyperalgesia (Cain et al., 2001).
Electrophysiological recording revealed that 34% of C-fibers devel-oped tumor-induced spontaneous activity and decreased thermal thresholds for activation, suggesting that the developing tumor causes C-fiber activation and sensitization (Cain et al., 2001).
This is partially dependent on the release of ET-1 at the tumor site (Hamamoto et al., 2008) and noradrenergic receptor activa-tion (Paice, 2003). The following secactiva-tion summarizes some of the peripheral mediators released at the tumor site that are responsible for cancer pain.
Endothelin-1
ET-1 is a vasoactive peptide that acts at peripheral sites via the G-protein-coupled receptors ET-A and ET-B. Endothelin-A recep-tors are implicated in the development of acute pain, vasoconstric-tion, and bronchoconstricvasoconstric-tion, and ET-B receptors are associated with inflammatory pain and vasodilation (Bagnato & Natali, 2004).
Both receptor types are found on dorsal root ganglion neurons (DRGs) and ET-B is also found on Schwann cells.
ET-1 injection excites nociceptors and enhances tumor-induced pain. Part of this hyperalgesic effect appears to occur via potenti-ation of transient receptor potential vanilloid subtype 1 (TRPV1)
Table 3.1. Neurochemical mediators and
electrophysiological changes that contribute to cancer pain
Peripheral sensitization ET-1
Bradykinin NGF
Cytokines: TNF-␣, IL-1, IL-6, G-CSF, GM-CSF ASIC
TRPV1 Osteoclasts
Others: prostanoids, COX, PAR-2 Central sensitization
Dynorphin Substance P CGRP
Glutamate/aspartate c-Fos expression Astrocyte hypertrophy ATP (P2X3)
TRPV1
NGF (TrkA receptors) Electrophysiology findings
↑WDR neuron responses
↑Receptive field size
↑NS neuron responses to non-noxious stimuli Alter NS:WDR neurons ratio
ASIC, acid-sensing ion channels; ATP, adenosine triphosphate;
CGRP, calcitonin gene-related peptide; COX, cyclooxygenase;
ET, endothelin; G-CSF, granulocyte colony-stimulating factor;
GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; NS, nonspiking; NGF, nerve growth factor; PAR-2, protease-activated receptor 2; TNF␣, tumor necrosis factor alpha;
TRPVI, transient receptor potential vanilloid subtype 1; WDR, wide dynamic range.
receptors located on nociceptive fibers (Wacnik et al., 2000; Pomo-nis et al., 2001; Peters et al., 2004). ET-1 is found in a number of different tumor types including prostatic (Yuyama et al., 2004), oral squamous cell carcinoma (Schmidt et al., 2007), melanoma (Schmidt et al., 2007), and renal, ovarian, and breast carcinoma (Bagnato & Natali, 2004). Additionally, even though ET-1 is not produced by all tumor types it is often present at the tumor site, and may contribute to the nociceptive process induced by the tumor (Kurbel et al., 1999; Asham et al., 2001; Davar, 2001; Wacnik et al., 2001; Zhou et al., 2001; Pickering et al., 2008). Increased concentrations of ET-1 and concomitant activation of primary affer-ent fibers were observed in a fibrosarcoma bone tumor model, but not in a control melanoma bone tumor model, where ET-1 con-centrations were undetectable (Wacnik et al., 2001). In addition, hyperalgesia was only observed in fibrosarcoma-implanted mice, and this hyperalgesia was significantly reduced by administration of an ET-A antagonist (Wacnik et al., 2001; Hasue et al., 2004;
Peters et al., 2004).
3 / Mechanisms of Cancer Pain 31
Cancer
Periphery
TrkA NGF
ATP
IL-1 P2X3 ETA
ET-1
DRASIC
Na+ channel MGIuR 1.5
Cortex
5-HT3
Spinal cord
Ascending Descending
Macrophage Dyn SP c-Fos CGRP Glut ATP TRPV1 Astrocyte TNF-α IL-1β TLR4
CGRP TNF G-CSF G M-CSF
Figure 3.1. The crucial components for inducing and maintaining cancer pain occur both peripherally and centrally. At the injury site, cancer cells release substances such as CGRP, tumor necrosis factor alpha (TNF-a), and granulocyte and
granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF). In addition, there are other substances released in the area such as nerve growth factor (NGF; binding to TrkA receptors), ATP (binding to P2X3receptors), and ET-1 (binding to ET-A receptors). Centrally, several substances are involved and receptors expressed, including dynorphin (Dyn),
substance P (SP), c-Fos expression, CGRP, glutamate (Glut), ATP, transient receptor potential vanilloid 1 (TRPV1) receptor expression, astrocyte migration, tumor necrosis factor (TNF-a), interleukin-1b (IL-1b), and toll-like receptor 4 (TLR4) expression. While pain perception is propagated to the higher brain levels via ascending pathways, the spinal cord also receives descending facilitation from the brain known to involve serotonin (5-HT3). Courtesy of Janis Atuk-Jones.
ET-1 causes excitation of C and A-␦fibers via ET-A receptors (Gokin et al., 2001), but a large dose of ET-1 can actually pro-duce antinociception via ET-B receptors (Piovezan et al., 2000).
Moreover, ET-A antagonists decreased mechanical hyperalgesia and ongoing pain behaviors, and ET-B antagonists enhanced these behaviors (Peters et al., 2004). Mechanical hyperalgesia, induced by prostatic cancer, can be attenuated by oral administration of an ET-A antagonist (Yuyama et al., 2004; Russo et al., 2010). Thus, it seems that antinociception in the periphery can be induced by administration of either ET-A antagonists or ET-B agonists (Gokin et al., 2001; Khodorova et al., 2002; Quang & Schmidt, 2010).
Endothelin-B agonists can significantly reduce pain for up to 3 hours after administration, and this effect is attenuated by admin-istration of a opioid receptor antagonist, suggesting that it is mediated by endogenous opioids (Quang & Schmidt, 2010). Inter-estingly, ET-B receptors are upregulated in certain types of can-cers (melanoma, ovarian, and breast cancer) (Wulfing et al., 2003;
Grimshaw et al., 2004), but downregulated in other types (squamous cell carcinoma, prostatic, colorectal, and bladder cancer) (Jeron-imo et al., 2003; Quang & Schmidt, 2010). Thus, the role of these
receptors in tumor-induced nociception may differ depending on the tumor type.
Bradykinin
Bradykinin is produced by melanoma cells, and is another vasoac-tive peptide with potent algogenic properties that appears to be involved in cancer pain. Bradykinin was shown to act on kinin B1 and B2 receptors on primary afferent neurons in a mouse model of skin cancer (Fujita et al., 2010). The release of bradykinin at the tumor site stimulates nerve fibers that innervate the tumor, and both bone-cancer-induced ongoing and movement-evoked nocifensive behaviors are reduced when the bradykinin B1 receptor is blocked (Sevcik et al., 2005). Additional information related to bradykinin and its interaction with ET-1 to cause pain can be found in the recent review by Schmidt et al. (2010a).
Nerve Growth Factor
NGF is involved in the regulation of neuronal function, synaptic plasticity, prevention of programmed cell death, and modulation and promotion of local growth and survival of sensory afferent
32 Section 1 / Introduction and Anatomy, Physiology, and Pathophysiology of Pain neurons (Levi-Montalcini et al., 1996). With many cancers,
includ-ing bone cancer, sensory neurons are chronically exposed to NGF (Jankowski & Koerber, 2010; Pantano et al., 2011), which leads to a number of changes in the microenvironment that contribute to pain. NGF binds directly to TRK and p75NTR receptors on primary sensory neurons. Mantyh et al. (2010) and Jimenez-Andrade et al.
(2011) have shown that early, sustained administration of anti-NGF blocks the pathological sprouting of sensory and sympathetic nerve fibers and the formation of neuroma-like structures in bone cancer, inhibiting the development of cancer pain.
Cytokines
It is likely that tumor-associated pain is, in part, driven by the inflammatory cascade and the release of various cytokines. Immune cells at the tumor site and tumor cells themselves release a number of cytokines and chemokines that appear to contribute to tumor-induced pain. Numerous cytokines are released from tumor cell lines including IL-1 (Fonsatti et al., 1997), IL-6 (Nasu et al., 1998), IL-8 (Nasu et al., 1998), tumor necrosis factor alpha (TNF-␣) (Basolo et al., 1993), and granulocyte and granulocyte-macrophage colony stimulating factor (G-CSF and GM-CSF) (Schweizerhof et al., 2009). TNF-␣is a proinflammatory cytokine released at the tumor site by various cell types, including mast cells, macrophages, endothelial cells, and fibroblasts, which stimulates immune cells and generates mechanical hyperalgesia (Wacnik et al., 2005). The TNF-␣receptors, TNFR1 and TNFR2, may be involved in main-taining thermal hyperalgesia (Constantin et al., 2008). Wacnik et al., (2005) demonstrated that fibrosarcoma-implanted animals exhibit an increased concentration of TNF-␣at the tumor site. Administra-tion of TNF-␣causes mechanical hyperalgesia in naive animals and increased hyperalgesia in animals with fibrosarcoma (Wacnik et al., 2005). In addition, administration of a TNF-␣antagonist attenuated TNF-␣associated thermal hyperalgesia without affecting the tumor size (Constantin et al., 2008).
Osteoclasts
Bone metastases are the most common cause of cancer-associated pain. Bone destruction caused by metastatic lesions occurs due to an increased rate of bone turnover in the absence of a complemen-tary increase in bone formation. Osteoclast activity is crucial for bone resorption (Mantyh, 2004); thus, if osteoclast activity could be inhibited, the resulting cancer-induced pain should be relieved (Clohisy & Ramnaraine, 1998; Honore et al., 2000). This can be accomplished with intravenous bisphosphonates, but the next gen-eration of bone metastasis treatments is in clinical development, and among them, the most advanced drug is denosumab. Denosumab is a human monoclonal antibody that inhibits osteoclast maturation and activation, and functions by binding to a receptor activator of nuclear factorB ligand, with the final result being a reduced rate of bone resorption (Castellano et al., 2011).
Acid-sensing Ion Channels and Transient Receptor Potential Vanilloid Subtype 1 Receptors
Acid-sensing ion channels (ASIC) (Mantyh et al., 2002; Garber, 2003; Sabino & Mantyh, 2005) and TRPV1 receptors (Asai et al., 2005; Ghilardi et al., 2005; Shinoda et al., 2008; Niiyama et al., 2009; Kawamata et al., 2010; Lotsch & Geisslinger, 2011) have been implicated in cancer pain. The presence of protons and an acidic environment (pH<6) are a distinctive feature of cancer,
and lead to the activation of TRPV1 receptors and ASIC channels (Caterina & Julius, 2001; Julius & Basbaum, 2001). The devel-opment of an acidic environment changes ASIC expression and sensitizes peripheral nociceptors (Julius & Basbaum, 2001; Nagae et al., 2007). The role of TRPV1 and ASICs as well as the acidic bone cancer environment in the development of bone cancer pain has recently been reviewed by Yoneda et al. (2011). Administra-tion of a TRPV1 antagonist attenuated tumor-induced pain behav-iors, suggesting that selective blockade of TRPV1 channels reduces cancer-induced pain (Ghilardi et al., 2005). Thus, TRPV1 and ASIC antagonists may be of therapeutic value, particularly with regard to bone cancer pain.
Other Mediators
A number of other mediators are present at many tumor sites, and probably contribute to the development of cancer pain. Prostanoids, proinflammatory derivatives of arachidonic acid, are released by cancer cells and bind to receptors on primary afferent neurons (Sabino et al., 2002; Urch, 2004). Similarly, proteases, secreted during inflammation, and their receptors, protease-activated recep-tor 2 (PAR-2), are also found on primary afferent neurons. PAR-2 causes thermal hyperalgesia via TRPV1 receptors. The blockade of protein kinase C and protein kinase A abolishes the sensitization of TRPV1 channels and attenuates thermal hyperalgesia precipitated by PAR activation (Amadesi et al., 2006). In addition to thermal hyperalgesia, it is also suggested that PAR-2 may cause mechani-cal hyperalgesia via the activation of TRPV4 channels (Grant et al., 2007).
Central Mechanisms of Cancer Pain Windup and Central Sensitization
Nociceptive input from the periphery reaches spinal cord neurons, where it is modified, and then carried by ascending pathways (the spinothalamic and spinocervicothalamic tracts) to supraspinal sites (Simone et al., 1991; Willis et al., 1999). Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, a phe-nomenon termed central sensitization (Woolf, 2011). The presence of either hyperalgesia or allodynia in a patient with cancer pain who has “spontaneous or ongoing” pain is highly indicative of cen-tral pain mechanisms. Part of this sensitization process involves
“windup” which is caused by repeated stimulation of peripheral nerve fibers, leading to progressively increasing electrical response in the corresponding spinal dorsal horn neurons. Windup has been proposed to be due to gradual recruitment of N-methyl-D-aspartate (NMDA) receptor activity, to summation of slow excitatory poten-tials mediated by substance P (SP) (and related peptides), and/or to facilitation of slow calcium channels by metabotropic glutamate receptors (Baranauskas & Nistri, 1998). The basis for central sen-sitization and the mechanisms underlying this phenomenon has recently been reviewed by Woolf (2011), and are discussed more fully in Chapter 2.
Bone cancer pain is one of the most painful types of tumor-induced pain (Medhurst et al., 2002; Vermeirsch et al., 2004). Pro-found neurochemical changes, reorganization of the spinal cord, and resulting widespread spinal sensitization may be the underly-ing mechanisms responsible for the development of chronic bone cancer pain (Schwei et al., 1999; Honore et al., 2000; Honore et al.,
3 / Mechanisms of Cancer Pain 33 2000; Luger et al., 2001). Prostate cancer can induce upregulation
of spinal cord IL-1expression (Zhang et al., 2005). Electrophysio-logical studies in prostate cancer reveal an increased responsiveness of wide dynamic range (WDR) neurons in the spinal cord in terms of spontaneous activity and responses to mechanical and thermal stim-uli (Khasabov et al., 2005). The responses of superficial WDR neu-rons, generally stimulated by non-noxious and noxious input, are dramatically enhanced, while deeper WDR neurons showed mini-mal changes, suggesting involvement of ascending and descending facilitation pathways (Urch et al., 2003; Urch et al., 2005). A recent study in a mouse model of bone cancer pain has shown that sub-stantia gelatinosa neurons in the spinal cord dorsal horn exhibited spontaneous excitatory postsynaptic currents (EPSCs) in tumor-bearing mice (Yanagisawa et al., 2010). The amplitudes of sponta-neous EPSCs were significantly larger in cancer-bearing compared to control mice, without any changes in passive membrane prop-erties of substantia gelatinosa neurons. The␣ -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)- and NMDA-mediated ESPCs were also enhanced in mice with cancer. This study, as well as others, indicates that widespread spinal sensitization may be one of the underlying mechanisms for the development of chronic bone, and other types of cancer pain.
Glia
A remarkable finding in animals with tumors is the develop-ment of a massive astrocyte hypertrophy in the ipsilateral spinal cord, which can be identified with glial fibrillary acidic protein (GFAP) immunostaining. Astrocyte hypertrophy occurs during cancer-induced bone destruction (Schwei et al., 1999; Zhang et al., 2005). Evidence suggests that the activation of glia contributes to central sensitization in the spinal cord (Watkins et al., 2001; Sessle, 2007; Watkins et al., 2007). The astrocyte hypertrophy observed in animal models of cancer pain is uncommonly seen with inflamma-tory or neuropathic pain and, therefore, represents a unique signa-ture of cancer pain. This GFAP expression is evident as early as day 17 after tumor inoculation (Medhurst et al., 2002). Exceptionally large astrocyte hypertrophy is obvious in bone cancer models, and is believed to partly play a role in cancer pain development and maintenance (Watkins et al., 2001).
Bone Metastasis
Bone metastasis is a serious complication of many neoplastic dis-eases such as breast, prostate, and lung cancer and a significant contributor to cancer pain.
Pain due to Cancer Invasion of Neural Tissues
Cancer invasion of surrounding tissues can occur during cancer progression, and has been reported in human patients with pancre-atic cancer (Zhu et al., 1999) and with vertebral metastasis (Zhu et al., 1999; Shimoyama et al., 2002). Invasion of neural tissue can lead to a neuropathic pain syndrome. Fibrosarcoma cells implanted near the sciatic nerve caused perineural invasion leading to the development of mechanical allodynia (Wacnik et al., 2000). Ani-mals implanted with sarcoma cells in close proximity to the sciatic nerves also demonstrate signs of spontaneous pain, for example, lifting and guarding of the painful area, as well as thermal allodynia and hyperalgesia (Shimoyama et al., 2002). Mechanical allodynia also occurs, and transitions into mechanical hypersensitivity after
2 weeks. Cancer-induced nerve invasion causes damage to myeli-nated and nonmyelimyeli-nated nerve fibers that is more extensive than damage caused by nerve ligation, suggesting that neoplastic nerve invasion may involve a mechanism other than direct nerve damage.
Chemotherapy- and Radiotherapy-Related Peripheral Neuropathy
Chemotherapy-induced peripheral neuropathies are dose-limiting adverse effects of many anticancer drugs. Vincristine, paclitaxel, and cisplatin produce chemotherapeutic-induced neuropathic pain in 30–70% of human patients undergoing chemotherapy (Polomano
& Bennett, 2001; Vadalouca et al., 2012). The underlying cause of this chemotherapy-induced neuropathy remains unclear. How-ever, it seems that the degree of chemotherapy-induced neuropathy varies with dose, treatment duration, and pre-existing conditions of the patient. Insight into neurotoxic mechanisms is critical to the development of new treatment and prevention strategies for chemotherapy-induced peripheral neuropathies.
Vincristine, a vinca alkaloid, is one of the most commonly used chemotherapeutic agents, and is reported to cause mechan-ical hyperalgesia (Authier et al., 1999; Higuera & Luo, 2004). This mechanical hyperalgesia developed as early as 2 weeks after intra-venous injection in rats, and ceased when vincristine was discon-tinued (Aley et al., 1996). Vincristine was also reported to produce greater mechanical hyperalgesia in female rats (Joseph & Levine, 2003). Interestingly, a continuous rate infusion of vincristine dose-dependently produced mechanical hyperalgesia, but not thermal hyperalgesia (Nozaki-Taguchi et al., 2001). This mechanical hyper-algesia could be attenuated by morphine or lidocaine administra-tion (Nozaki-Taguchi et al., 2001), but not byopioid antagonists (Aley et al., 1996). A recent comparison of vincristine-induced peripheral neuropathy and that induced by another anticancer agent, bortezomib, using gene expression profiling, suggests that the fac-tors involved in the development of peripheral neuropathy are dis-tinct, and involve different molecular mechanisms (Richardson, 2010).
Paclitaxel is commonly used to treat solid tumors, and its adverse effects include myelosuppression and peripheral neuropathy (Polo-mano & Bennett, 2001). In addition, human patients who received paclitaxel complained of numbness and burning pain (Polomano
& Bennett, 2001). Paclitaxel-induced neuropathy lasts for several weeks and is limited to peripheral nerves, with the animals showing no systemic toxicity or axonal degeneration (Cavaletti et al., 1995;
Polomano & Bennett, 2001; Xiao & Bennett, 2008). Behavioral signs include mechanical hyperalgesia and thermal hyperalgesia without motor deficits (Polomano & Bennett, 2001).
Cisplatin causes peripheral neuropathy and mechanical hyperal-gesia (Authier et al., 2000) by affecting large myelinated axons, but has no effect on nonmyelinated axons. In addition, cisplatin decreases nerve conduction velocity of peripheral sensory nerves, but not motor nerves (de Koning et al., 1987a; de Koning et al., 1987b; Authier et al., 2003).
POTENTIAL FUTURE TREATMENTS
TRPV1 is a nonselective cation channel that is found on primary afferent neurons. It plays an important role in pain sensitivity of sensory neurons in the periphery (Premkumar & Sikand, 2008).
Ablating the DRG neurons expressing TRPV1 receptors may be
34 Section 1 / Introduction and Anatomy, Physiology, and Pathophysiology of Pain an effective treatment for controlling chronic cancer pain, while
leaving other sensory functions intact (Karai et al., 2004; Ghilardi et al., 2005). Dogs with spontaneous bone cancer developed pro-found analgesia for up to 3.5 months after intrathecal treatment with the capsaicin analog resiniferatoxin, a potent TRPV1 agonist (Brown et al., 2005).
The concept of selective DRG neuron ablation has been used by some laboratories for targeting other neurons, for example, neu-rons expressing NK-1 receptors. These approaches have shown no adverse effects in either rat or dog models (Khasabov et al., 2005;
Allen et al., 2006).
ALLEVIATION OF CANCER PAIN
Cancer-pain treatment guidelines provided by the World Health Organization (WHO) include the use of opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, local anesthetics, antidepressants, and anticonvulsants, either alone or in combina-tion. These current conventional therapies may not be effective in controlling cancer pain, and they may have significant adverse effects. One of the contributing factors making cancer pain diffi-cult to treat is that it is a mixed-pain syndrome having nociceptive, inflammatory, and neuropathic components (Paice, 2003). There-fore, a combination of treatment approaches is warranted.
The development and maintenance of cancer pain is a dynamic process. Alleviation of cancer pain may have to be based on dis-ease progression. At the early stage of tumor growth, as tumors start to proliferate, pronociceptive factors (PGE2and ET) are released.
Therefore, COX inhibitors or ET antagonists may be effective treat-ments during this period. In later stages, when tumors are grow-ing and compressgrow-ing surroundgrow-ing nerve bundles, neuropathic pain medications may provide better pain control. When tumors fill the intramedullary canal and dead tumor cells produce an acidic environment, TRPV1 or ASIC receptor antagonists may be bene-ficial in controlling pain. Once bone destruction becomes evident, ATP antagonists (ATP, present during cancer growth, is an endoge-nous ligand for P2X (membrane ion channel) receptors) may block movement-related pain (Mantyh, 2004; Mantyh & Hunt, 2004).
Interesting therapeutic options also include targets on nociceptive afferents that innervate the bone, such as TRPV1, Trk, and cannabi-noid receptors. Newly discovered therapeutic treatments developed based on our current understanding of these mechanisms, such as resiniferatoxin or saporin (SAP; causing ablation of SP-expressing cells by conjugating a toxin, saporin, into SP), may yield promising results.
The newly developed gene database based on the knockout of individual mouse genes allows investigators to study pain-related phenotypes associated with specific genes, generating a better understanding of the roles that these genes and their protein prod-ucts have in pain processing and modulation. This information will be crucial to developing novel therapeutic drugs targeting specific genes for particular types of cancer pain (Lacroix-Fralish et al., 2007). See Chapter 27 for discussion of treatment of cancer pain.
SUMMARY
Cancer pain mechanisms are complicated. Cancer itself can induce pain both peripherally and centrally. There are many substances or mediators released during cancer growth that induce and
main-tain cancer pain. In addition, cancer pain may occur indirectly via chemotherapy, and coexisting painful conditions may be present.
Understanding these complex mechanisms is necessary to effec-tively control and manage pain. Further studies are required to better understand the distinctive molecular mechanisms of cancer pain in order to target specific sites or mechanistic pathways with pharmacological agents.
ACKNOWLEDGMENT
We thank Janis Atuk-Jones for her image production assistance.
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