Articles: hyperalgesia-pathology.
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Primary and metastatic cancers that affect bones are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. In the present study, we investigated whether inhibition of KCNQ/M (Kv7) potassium channels in the spinal cord contributes to the development of bone cancer pain via sensitization of dorsal horn wide dynamic range (WDR) neurons. ⋯ Furthermore, we discovered that blockade of KCNQ/M channels in the spinal cord by local administration of XE-991, a specific KCNQ/M channel blocker, caused a robust increase in excitability of dorsal horn WDR neurons, while, producing obvious pain hypersensitivity in normal rats. On the contrary, activation of spinal KCNQ/M channels by retigabine, a selective KCNQ/M channel opener, not only inhibited the bone cancer‑induced hyperexcitability of dorsal horn WDR neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in the bone cancer rats, while all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. All things considered, these results suggest that suppression of KCNQ/M channels in the spinal cord likely contributes to the development of bone cancer pain via sensitization of dorsal horn WDR neurons in rats following tumor cell inoculation.
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Spinal nerve L5/L6 ligation (SNL) in rats has become the standard for mechanistic studies of peripheral neuropathy and screening for novel analgesics. Conventional SNL in our hybrid mice resulted in a wide range of allodynia. Anatomical evaluation indicated that a variable number of lumbar vertebrae existed, resulting in L4/L5 or L5/L6 being ligated. ⋯ Ligation of mouse L4 and L5 spinal nerves produces consistent, robust neuropathic pain behaviors and is suitable as a model for investigating mechanisms of neuropathic pain and for testing of novel analgesics. Gabapentin, used as a validation drug in neuropathic pain models and as a reference compound for novel analgesics, significantly reduced allodynia in the mice tested (L4/L5 ligations). Given the ease of surgery, robust allodynia, and larger von Frey sensitive area, we conclude that combined ligation of spinal nerves L4 and L5 optimizes the SNL model in mice.
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Hyperalgesia in different musculoskeletal structures including bones is a major clinical problem. An experimental bone hyperalgesia model was developed in the present study. Hyperalgesia was induced by three different weights impacted on the shinbone in 16 healthy male and female subjects. ⋯ Females developed more pronounced hyperalgesia reflected in reduced IPTs and PPTs (p < 0.05). Temporal summation was significantly (p < 0.05) facilitated after induction of hyperalgesia with the strongest facilitation in males. The developed bone pain and hyperalgesia model may provide the basis for studying this fundamental mechanism of bone-related hyperalgesia and be used for profiling compounds developed for this target.
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Polyneuropathy is a frequent and potentially severe side effect of clinical tumor chemotherapy. The goal of this study was to characterize paclitaxel-, cisplatin-, vincristine- and bortezomib-induced neuropathy in C57BL/6 mice with a comparative approach. The phenotype of the animals was evaluated at four time points with behavioral and electrophysiological tests, followed by histology. ⋯ This finding was confirmed by histological analysis of the sciatic nerve which showed predominantly axonal damage: Paclitaxel and vincristine affected mostly large myelinated fibers, bortezomib small myelinated fibers and cisplatin damaged all types of myelinated fibers to a similar degree. Neuropathic symptoms developed faster in paclitaxel and vincristine treated animals compared to cisplatin and bortezomib treatment. The animal models in this study can be used to elucidate pathomechanisms underlying chemotherapy-induced polyneuropathy and for the development of novel therapeutic and preventative strategies.