Articles: hyperalgesia.
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Translational models of the sensitized pain system are needed to progress the understanding of involved mechanisms. In this study, long-term potentiation was used to develop a mechanism-based large-animal pain model. Event-related potentials to electrical stimulation of the ulnar nerve were recorded by intracranial recordings in pigs, 3 weeks before, immediately before and after, and 3 weeks after peripheral high-frequency stimulation (HFS) applied to the ulnar nerve in the right forelimb (7 pigs) or in control animals (5 pigs). ⋯ The relative increase in N1 30 minutes after HFS and the degree of mechanical hyperalgesia 2 weeks post-HFS was correlated ( P < 0.033). These results show for the first time that the pig HFS model resembles the human HFS model closely where the profile of sensitization is comparable. Interestingly, the degree of sensitization was associated with the cortical signs of hyperexcitability at HFS induction.
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Painful neuropathy is a pathological condition caused by numerous factors including diabetes, chemotherapy or cancer. ART26.12 is a novel fatty acid-binding protein 5 inhibitor, which our group showed could prevent and treat persistent pain in a preclinical model of oxaliplatin-induced peripheral neuropathy. ⋯ This work now shows that ART26.12, a novel and selective inhibitor of FABP5, can prevent and treat multiple preclinical models of peripheral neuropathy. Given its excellent safety profile, further work is warranted to develop ART26.12 as a potential therapeutic tool for pain management.
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As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. ⋯ Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain.
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Cold allodynia is a common complaint of patients suffering from neuropathic pain initiated by peripheral nerve injury. However, the mechanisms that drive neuropathic cold pain remain elusive. In this study, we show that the interleukin (IL)-33/ST2 signaling in the dorsal root ganglion (DRG) is a critical contributor to neuropathic cold pain by interacting with the cold sensor transient receptor potential melastatin 8 (TRPM8). ⋯ Co-immunoprecipitation assays further reveal that ST2 interacts with TRPM8 in DRG neurons. Importantly, rIL-33-induced cold allodynia is abolished by pharmacological inhibition of TRPM8 and genetic ablation of the TRPM8-expressing neurons. Thus, our findings suggest that the IL-33/ST2 signaling mediates neuropathic cold pain through downstream cold-sensitive TRPM8 channels, thereby identifying a potential analgesic target for the treatment of neuropathic cold pain.