Chemical Interactions between Fibrosarcoma Cancer Cells and Sensory Neurons Contribute to Cancer Pain

Khasabova, Iryna A.; Stucky, Cheryl L.; Harding-Rose, Catherine; Eikmeier, Laura; Beitz, Alvin J.; Coicou, Lia G.; Hanson, Amy E.; Simone, Donald A.; Seybold, Virginia S.

doi:10.1523/jneurosci.2851-07.2007

Cited by 59 publications

(78 citation statements)

References 68 publications

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“…Although we cannot rule out the possibility that mechanically-insensitive nociceptors developed mechanical sensitivity as a result of tumor growth, our data suggest that mechanical hyperalgesia in this model of cancer pain may result from central sensitization. Indeed, we have shown that wide dynamic range neurons in the dorsal horn of the spinal cord exhibited enhanced responses to mechanical stimuli (Khasabov et al, 2007). Attenuation of tumor-evoked mechanical hyperalgesia by peripheral administration of WIN 55,212-2 appears to be mediated by reduced spontaneous activity in C-fiber nociceptors which may decrease the C-fiber drive to maintain the sensitization of nociceptive dorsal horn neurons, and by a decrease in responses of C-fibers evoked by mechanical stimuli.…”

Section: Discussionmentioning

confidence: 99%

The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain

et al. 2013

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Pain from cancer can be severe, difficult to treat, and greatly diminishes patients’ quality of life. It is therefore important to gain new information on the mechanisms of cancer pain and develop new treatment strategies. We have used a murine model of bone cancer pain to investigate underlying peripheral neural mechanisms and novel treatment approaches. In this model, implantation of fibrosarcoma cells into and around the calcaneous bone produces mechanical and thermal hyperalgesia in mice. C-fiber nociceptors in tumor-bearing mice develop spontaneous ongoing activity and sensitization to thermal stimuli. However, it is unclear whether sensitization of nociceptors to mechanical stimuli underlies the mechanical hyperalgesia seen in tumor-bearing mice. We therefore examined responses of C-fiber nociceptors to suprathreshold mechanical stimuli in tumor-bearing mice and found they did not differ from those of C-nociceptors in control mice. Thus, sensitization of C-fiber nociceptors to mechanical stimulation does not appear to underlie tumor-evoked mechanical hyperalgesia in this murine model of bone cancer pain. We also examined the effect of the non-selective cannabinoid receptor agonist, WIN 55, 212-2, on spontaneous activity and responses evoked by mechanical stimuli of C-fiber nociceptors innervating the tumor-bearing paw. Selective CB1 and CB2 antagonists were administered to determine the contribution of each receptor subtype to the effects of WIN 55,212-2. Intraplantar administration of WIN 55,212-2 attenuated spontaneous discharge and responses evoked by mechanical stimulation of C-fiber nociceptors. These effects were inhibited by prior intraplantar administration of selective CB1 (AM281) or CB2 (AM630) receptor antagonists but not by vehicle. These results indicate that activation of either CB1 or CB2 receptors reduced the spontaneous activity of C-fiber nociceptors associated with tumor growth as well as their evoked responses. Our results provide further evidence that activation of peripheral cannabinoid receptors may be a useful target for the treatment of cancer pain.

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Section: Discussionmentioning

confidence: 99%

The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain

et al. 2013

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“…Cultures were prepared from DRGs collected from all levels of the spinal cord as previously described [35]. Cells in the final suspension were plated at a density equivalent to ~3 DRGs/laminin-coated glass coverslip for biochemical studies.…”

Section: Methodsmentioning

confidence: 99%

JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy

Khasabova

Yao

Paz

et al. 2014

Pharmacological Research

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Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1 mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [3H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [3H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.

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“…More recent evidence supporting a key role for chemokines and their receptors in chronic pain has come from the results of experiments using several accepted models of neuropathic pain in rodents. These models include sciatic nerve transaction (54,55), partial ligation of the sciatic nerve (26,56,57), chronic constriction injury of the sciatic nerve (58)(59)(60) (61,62), and zymosan-induced inflammatory pain (58,63,64). Each of these models resulted in up-regulation of one or more chemokine receptors by DRG neurons associated with, or in close proximity to, the injury.…”

Section: Chemokines and Their Receptors In Acute And Chronic Painmentioning

confidence: 99%

Chemokines and the pathophysiology of neuropathic pain

White

Jung²,

Miller

2007

Proc. Natl. Acad. Sci. U.S.A.

326

266

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Chemokines and chemokine receptors are widely expressed by cells of the immune and nervous systems. This review focuses on our current knowledge concerning the role of chemokines in the pathophysiology of chronic pain syndromes. Injury-or disease-induced changes in the expression of diverse chemokines and their receptors have been demonstrated in the neural and nonneural elements of pain pathways. Under these circumstances, chemokines have been shown to modulate the electrical activity of neurons by multiple regulatory pathways including increases in neurotransmitter release through Ca-dependent mechanisms and transactivation of transient receptor channels. Either of these mechanisms alone, or in combination, may contribute to sustained excitability of primary afferent and secondary neurons within spinal pain pathways. Another manner in which chemokines may influence sustained neuronal excitability may be their ability to function as excitatory neurotransmitters within the peripheral and central nervous system. As is the case for traditional neurotransmitters, injury-induced up-regulated chemokines are found within synaptic vesicles. Chemokines released after depolarization of the cell membrane can then act on other chemokine receptor-bearing neurons, glia, or immune cells. Because up-regulation of chemokines and their receptors may be one of the mechanisms that directly or indirectly contribute to the development and maintenance of chronic pain, these molecules may then represent novel targets for therapeutic intervention in chronic pain states. In his landmark treatise Sir Charles Scott Sherrington proposed the concept that pain is the evolved response to a potentially harmful, noxious stimulus (1). An example would be placing your hand on a hot iron and the resulting sensation of pain, which produces almost immediate withdrawal, thereby preventing tissue damage. This conscious perception of pain is the result of activity in a set of well defined neural pathways that start with the primary afferent neurons. These pseudounipolar neurons are responsible for the transmission of pain (''nociceptors'') and have unmyelinated or lightly myelinated axons. The cell bodies of nociceptors are found in the dorsal root ganglia (DRG). Nociceptors have both a peripheral connection that innervates potentially diseased or traumatized nerves, muscles, tendons, organs, and epithelia, and a centrally projecting axon that enters the central nervous system. This central axon conveys ''nociceptive'' information to second-order neurons in the dorsal horn of the spinal cord. Neural connections from the dorsal horn to the thalamus, and from there to the cortex, relay this noxious information to higher centers of conscious experience (Fig. 1). The central axons of primary afferent nociceptive neurons also provide information to polysynaptic spinal cord interneurons, which are essential for the initiation of the nociceptive withdrawal reflex. These neurons trigger motor reflexes that are important in the avoidance of potentially harmful ...

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Chemical Interactions between Fibrosarcoma Cancer Cells and Sensory Neurons Contribute to Cancer Pain

Abstract: In an experimental model of cancer pain, the hyperalgesia that occurs with osteolytic tumor growth is associated with the sensitization of nociceptors. We examined functional and molecular changes in small-diameter dorsal root ganglion (

Cited by 59 publications

References 68 publications

The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain

The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain

JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy

Chemokines and the pathophysiology of neuropathic pain

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