Pain
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The ability to sense and respond to thermal stimuli at varied environmental temperatures is essential for survival in seasonal areas. In this study, we show that mice respond similarly to ramping changes in temperature from a wide range of baseline temperatures. ⋯ The adjustment of this set point requires transient receptor potential cation channel, subfamily member 8 (TRPM8), but not transient receptor potential cation channel, subfamily A, member 1 (TRPA1), and is regulated by phospholipase C (PLC) activity. Overall, our findings suggest that temperature response thresholds in mice are dynamic, and that this ability to adapt to environmental temperature seems to mirror the in vitro findings that PLC-mediated hydrolysis of phosphoinositol 4,5-bisphosphate modulates TRPM8 activity and thereby regulates the response thresholds to cold stimuli.
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The transient receptor potential vanilloid receptor type-1 (TRPV1) is critically involved in peripheral nociceptive processes of somatic and visceral pain. However, the role of the capsaicin receptor in the brain regarding visceral pain remains elusive. ⋯ Notably, intracerebral TRPV1 antagonism by SB 366791 significantly reduced chemical and inflammatory spontaneous abdominal nocifensive responses, as observed by reduced expressions of nociceptive facial grimacing, illustrating the affective component of pain. In addition to the established role of cerebral TRPV1 in anxiety, fear, or emotional stress, we demonstrate here for the first time that TRPV1 in the brain modulates visceral nociception by interfering with the affective component of abdominal pain.
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Comparative Study
The Anti-Hyperalgesic Effects of a Novel TRPM8 Agonist in Neuropathic Rats: A Comparison with Topical Menthol.
Menthol has historically been used topically to alleviate various pain conditions. At low concentrations, this non-selective TRPM8 agonist elicits a cooling sensation, however higher concentrations result in cold hyperalgesia in normal subjects and paradoxically analgesia in neuropathic patients. Through behavioural and electrophysiological means, we examined whether this back-translated into a pre-clinical rodent model. ⋯ In addition, M8-Ag attenuated behavioural hypersensitivity to innocuous cooling but not mechanical stimulation. These data suggest that menthol induced hyperalgesia is not consistently replicable in the rat and that the analgesic properties are revealed by injury. Systemic TRPM8 agonists might be beneficial in neuropathy without affecting normal cold sensitivity.
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Emerging lines of evidence indicate that production of reactive oxygen species (ROS) at distinct sites of the nociceptive system contributes to the processing of neuropathic pain. However, the mechanisms underlying ROS production during neuropathic pain processing are not fully understood. We here detected the ROS-generating nicotinamide adenine dinucleotide phosphate oxidase isoform Nox2 in macrophages of dorsal root ganglia (DRG) in mice. ⋯ Nox2-deficient mice displayed reduced neuropathic pain behavior after peripheral nerve injury, whereas their immediate responses to noxious stimuli were normal. Moreover, injury-induced upregulation of tumor necrosis factor α was absent, and activating transcription factor 3 induction was reduced in DRG of Nox2-deficient mice, suggesting an attenuated macrophage-neuron signaling. These data suggest that Nox2-dependent ROS production in macrophages recruited to DRG contributes to neuropathic pain hypersensitivity, underlining the observation that Nox-derived ROS exert specific functions during the processing of pain.