The TRPA1 Channel Mediates Mechanical Allodynia and Thermal Hyperalgesia in a Rat Bone Cancer Pain Model

Abstract

Background: Bone cancer pain (BCP) significantly affects patient quality of life, results in great bodily and emotional pain, and creates difficulties in follow-up treatment and normal life. Transient receptor potential ankyrin 1 (TRPA1) is an essential transduction ion channel related to neuropathic and inflammatory pain. However, the role of TRPA1 in BCP remains poorly understood. This study aimed to explore the relationship between TRPA1 and BCP.Methods: A BCP model was induced by Walker256 cells to the left tibia. The sham group was induced by normal saline to the left tibia. Thereafter, pain behaviors and TRPA1 expression between the BCP group and the sham group were observed on the 14th day of modeling. The TRPA1 antagonist A967079 (10 mg/kg) was injected via tail vein. TRPA1 antisense oligodeoxynucleotide (AS-ODN, 5 nmol/10 μl) and missense oligodeoxynucleotide (MS-ODN, 5 nmol/10 μl) were intrathecally delivered via a mini-osmotic pump for 5 consecutive days to assess the effect of TRPA1 on BCP. Behavioral tests were assessed preoperatively and postoperatively. Real-time quantitative PCR and western blot analyses were used to measure TRPA1 levels among the different groups.Results: The BCP model was successfully established via X-ray and pathological sections at 14 days. Compared to the sham group, the BCP group was more sensitive to mechanical stimuli, cool stimuli and hot stimuli. Intravenously injected A967079 can relieve paw mechanical withdrawal threshold and paw withdrawal thermal latency in rats with BCP. Moreover, AS-ODN can relieve paw mechanical withdrawal threshold and paw withdrawal thermal latency in rats with BCP. Additionally, relative mRNA and protein expression of TRPA1 in the BCP group were much higher than those in the sham group (14.55 ± 1.97 vs. 1 ± 0.04, P < 0.01). Compared to the BCP group, the relative mRNA and protein expression of TRPA1 in the BCP+AS-ODN group was reduced (14.55 ± 1.97 vs. 2.59 ± 0.34, P < 0.01).Conclusions: The TRPA1 channel mediates mechanical allodynia and thermal hyperalgesia in a rat BCP model.

Toll-like receptor 4 signaling pathway in sensory neurons mediates remifentanil-induced postoperative hyperalgesia via transient receptor potential ankyrin 1

“… 38 , 39 Although TRPA1 serves as a key detector of mechanical and chemical stimuli, the thermal sensitivity of TRPA1 remains controversial. 40 Recent evidence put forward the hypothesis that mammalian TRPA1 may be activated by noxious cold and noxious heat, 41 , 42 which was not in accordance with this hypothesis. These data suggested that thermal hyperalgesia in RIH might result from other mechanisms independent of TLR4 and TRPA1, which should be further investigated in the following studies.…”

Modelling skeletal pain harnessing tissue engineering

“…Bone fracture in rodent models is performed using tailored protocols where the selected bone segment is broken using a defined force [132,144,145]. The most common fracture Mice with injection of Lewis lung cancer (LLC) Adeno-associated virus shANXA3 (AAV-shANXA3) [134] Mice subject to chemotherapy-induced peripheral neuropathy Hsp90 inhibitors [135] SD rats with Walker256 tumour tibial injection TRPA1 antisense oligodeoxynucleotide delivery [136] BALB/cAnNHsd mice with 66.1 breast cancer cells…”

“…Targeting via TRPA1 antisense oligodeoxynucleotide (AS-ODN) relieved PMWT and PWTL. Adapted from [ 136 ]. Copyright© 2021 under the terms of the Creative Commons Attribution License (CC BY).…”

“…5 b ). Approaches include the Transient receptor potential ankyrin 1 (TRPA1), recently targeted by Liu and co-workers [ 136 ] using TRPA1 antagonist and antisense oligodeoxynucleotide. Nevertheless, poor translation to human pathophysiology remains impairing pre-clinical drug screening and, crucially, validation.…”

Druggable Targets and Compounds with Both Antinociceptive and Antipruritic Effects

“…It is also expressed in the non-neuronal tissues such as fibroblasts, pancreas, lung, urinary tract, and endothelium. In several animal studies, TRPA1-deficient mice exhibited attenuated pain responses to formalin, noxious cold, and tactile force [ 105 , 106 , 107 , 108 ]. Corresponding evidence was reported in a study of gain-of-function N855S mutation on TRPA1 in patients with familial episodic pain syndrome [ 109 ].…”