Mechanism of cancer pain.

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.

Changes in response properties of nociceptive dorsal horn neurons in a murine model of cancer pain.

Pain associated with cancer that metastasizes to bone is often severe and debilitating. A better understanding of the neural mechanisms that mediate cancer pain is needed for the development of more effective treatments. In this study, we used an established model of cancer pain to characterize changes in response properties of dorsal horn neurons. Fibrosarcoma cells were implanted into and around the calcaneus bone in mice and extracellular electrophysiological recordings were made from wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons. Responses of WDR and HT neurons evoked by mechanical, heat, and cold stimuli applied to the plantar surface of the hind paw were compared between tumor bearing mice and control mice. Mice exhibited hyperalgesia to mechanical and heat stimuli applied to their tumor-bearing hind paw. WDR neurons in tumor-bearing mice exhibited an increase in spontaneous activity, and enhanced responses to mechanical, heat, and cold stimuli as compared to controls. Our findings show that sensitization of WDR neurons, but not HT neurons, contributes to tumor-evoked hyperalgesia.

Tumor-evoked sensitization of C nociceptors: a role for endothelin.

Primary and metastatic cancers that effect bone are frequently associated with pain. Sensitization of primary afferent C nociceptors innervating tissue near the tumor likely contributes to the chronic pain and hyperalgesia accompanying this condition. This study focused on the role of the endogenous peptide endothelin-1 (ET-1) as a potential peripheral algogen implicated in the process of cancer pain. Electrophysiological response properties, including ongoing activity and responses evoked by heat stimuli, of C nociceptors were recorded in vivo from the tibial nerve in anesthetized control mice and mice exhibiting mechanical hyperalgesia following implantation of fibrosarcoma cells into and around the calcaneus bone. ET-1 (100 microM) injected into the receptive fields of C nociceptors innervating the plantar surface of the hind paw evoked an increase in ongoing activity in both control and tumor-bearing mice. Moreover, the selective ETA receptor antagonist, BQ-123 (3 mM), attenuated tumor-evoked ongoing activity in tumor-bearing mice. Whereas ET-1 produced sensitization of C nociceptors to heat stimuli in control mice, C nociceptors in tumor-bearing mice were sensitized to heat, and their responses were not further increased by ET-1. Importantly, administration of BQ-123 attenuated tumor-evoked sensitization of C nociceptors to heat. We conclude that ET-1 at the tumor site contributes to tumor-evoked excitation and sensitization of C nociceptors through an ETA receptor mediated mechanism.

Tumor-evoked hyperalgesia and sensitization of nociceptive dorsal horn neurons in a murine model of cancer pain.

Pain associated with cancer, particularly when tumors metastasize to bone, is often severe and debilitating. Better understanding of the neurobiological mechanisms underlying cancer pain will likely lead to the development of more effective treatments. The aim of this study was to characterize changes in response properties of nociceptive dorsal horn neurons following implantation of fibrosarcoma cells into and around the calcaneus bone, an established model of cancer pain. Extracellular electrophysiological recordings were made from wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons in mice with tumor-evoked hyperalgesia and control mice. WDR and HT neurons were examined for ongoing activity and responses to mechanical, heat, and cold stimuli applied to the plantar surface of the hind paw. Behavioral experiments showed that mice exhibited hyperalgesia to mechanical and heat stimuli applied to their tumor-bearing hind paw. WDR, but not HT, nociceptive dorsal horn neurons in tumor-bearing mice exhibited sensitization to mechanical, heat, and cold stimuli and may contribute to tumor-evoked hyperalgesia. Specifically, the proportion of WDR neurons that exhibited ongoing activity and their evoked discharge rates were greater in tumor-bearing than in control mice. In addition, WDR neurons exhibited lower response thresholds for mechanical and heat stimuli, and increased responses to suprathreshold mechanical, heat, and cold stimuli. Our findings show that sensitization of WDR neurons contributes to cancer pain and supports the notion that the mechanisms underlying cancer pain differ from those that contribute to inflammatory and neuropathic pain.

Acute and chronic administration of the cannabinoid receptor agonist CP 55,940 attenuates tumor-evoked hyperalgesia.

Patients with cancer frequently report pain that can be difficult to manage. This study examined the antihyperalgesic effects of a cannabinoid receptor agonist, CP 55,940, in a murine model of cancer pain. Implantation of fibrosarcoma cells into and around the calcaneous bone in mice produced mechanical hyperalgesia (decreased paw withdrawal thresholds and increased frequency of paw withdrawals). On day 13 after implantation, mechanical hyperalgesia, nociception, and catalepsy were assessed. Mice were randomly assigned to receive CP 55,940 (0.01-3 mg/kg, i.p.) or vehicle and behavioral measures were redetermined. CP 55,940 dose-dependently attenuated tumor-evoked mechanical hyperalgesia. To examine the effect of catalepsy on the antihyperalgesic effect of CP 55,940, mice with tumor-evoked hyperalgesia were pretreated with the dopamine agonist apomorphine prior to administration of CP 55,940. Apomorphine attenuated the cataleptic effect of CP 55,940 but did not attenuate its antihyperalgesic effect. In a separate group of mice with tumor-evoked hyperalgesia, administration of the dopamine antagonist spiperone produced catalepsy that was approximately 2.5 fold greater than that produced by CP 55,490. Whereas this dose of CP 55,940 completely reversed tumor-evoked mechanical hyperalgesia, spiperone only attenuated mechanical hyperalgesia by approximately 35%. Thus, the cataleptic effects of CP 55,940 did not fully account for its antihyperalgesic effect. The antihyperalgesic effect of CP 55,940 was mediated via the cannabinoid CB1 but not CB2 receptor. Finally, repeated administration of CP 55,940 produced a short-term and a longer-term attenuation of tumor-evoked hyperalgesia. These results suggest that cannabinoids may be a useful alternative or adjunct therapy for treating cancer pain.

A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain.

Pain associated with cancer and chronic musculoskeletal disorders can be difficult to control. We used murine models of cancer and inflammatory muscle pain to examine whether the cannabinoid receptor agonist WIN55,212-2 reduces hyperalgesia originating in deep tissues. C3H/He mice were anesthetized and implanted with osteolytic NCTC clone 2472 cells into the humeri or injected with 4% carrageenan into the triceps muscles of both forelimbs. At the time of peak hyperalgesia, WIN55,212-2 (1-30mg/kg) or vehicle was administered intraperitoneally and forelimb grip force was measured 0.5-24h later. WIN55,212-2 produced time- and dose-related antihyperalgesia in both models. A 10mg/kg dose of WIN55,212-2 fully reversed carrageenan-evoked muscle hyperalgesia. However, 30mg/kg of WIN55,212-2 attenuated tumor-evoked hyperalgesia only approximately 50%. After controlling for the difference in magnitude of hyperalgesia between the two models, WIN55,212-2 was still more potent at reducing hyperalgesia in the inflammatory model. In the cancer pain model, the antihyperalgesic effect of WIN55,212-2 was partially blocked by pretreatment with the selective CB1 (SR141716A) but not the CB2 (SR144528) receptor antagonist. In contrast, both antagonists blocked antihyperalgesic effects of WIN55,212-2 on carrageenan-evoked muscle hyperalgesia. Catalepsy and loss of motor coordination, known side effects of cannabinoids, did not account for the antihyperalgesia produced by WIN55,212-2. These data show that cannabinoids attenuate deep tissue hyperalgesia produced by both cancer and inflammatory conditions. Interestingly, cannabinoids differentially modulated carrageenan- and tumor-evoked hyperalgesia in terms of potency and receptor subtypes involved suggesting that differences in underlying mechanisms may exist between these two models of deep tissue pain.