Dataset Information

Mast cell stabilizer ketotifen fumarate reverses inflammatory but not neuropathic-induced mechanical pain in mice.

ABSTRACT:

Introduction

Mast cell (MC) activation could establish a positive feedback loop that perpetuates inflammation and maintains pain. Stabilizing MCs with ketotifen fumarate (KF) may disrupt this loop and relieve pain.

Objective

We aimed to test the effect of treatment with KF in pain assays in mice and in a case series of patients with chronic widespread pain.

Methods

The analgesic effect of KF was tested in CD-1 mice injected with formalin, complete Freund's adjuvant, or subjected to spared nerve injury. In addition, wild-type (C57BL/6) and MC-deficient (C57BL/6-Kit ^W-sh/W-sh) mice were injected with formalin or complete Freund's adjuvant and treated with KF. Patients with chronic widespread pain (n = 5; age: 13-16 years) who failed to respond to standard of care participated in a 16-week treatment trial with KF (6 mg/d). Ketotifen fumarate's therapeutic effect was evaluated using the patient global impression of change.

Results

In the mouse experiments, KF produced dose- and MC-dependent analgesic effects against mechanical allodynia in the acute and chronic inflammatory pain but not neuropathic pain assays. In the patient case series, 4 patients reported that activity limitations, symptoms, emotions, and overall quality of life related to their pain condition were "better" or "a great deal better" since beginning treatment with KF. This was accompanied by improvements in pain comorbid symptoms.

Conclusion

Treatment with KF is capable of reducing established inflammatory-induced mechanical nociception in an MC-dependent manner in mice, and it may be beneficial for the treatment of chronic pain conditions.

SUBMITTER: Meloto CB

PROVIDER: S-EPMC8177879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAvailable treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic node for neuropathic pain, the authors focused on the master regulator of the antioxidant response-nuclear factor erythroid 2-related factor 2 (NFE2L2; Nrf2)-as an alternative target for neuropathic pain. The authors tested whether dimethyl fumarate (U.S. Food and Drug Administration-approved treatment for multiple sclerosis) would activate NFE2L2 and promote antioxidant activity to reverse neuropathic pain behaviors and oxidative stress-dependent mechanisms.MethodsMale Sprague Dawley rats, and male and female wild type and Nfe2l2 mice were treated with oral dimethyl fumarate/vehicle for 5 days (300 mg/kg; daily) after spared nerve injury/sham surgery (n = 5 to 8 per group). Allodynia was measured in von Frey reflex tests and hyperalgesia in operant conflict-avoidance tests. Ipsilateral L4/5 dorsal root ganglia were assayed for antioxidant and cytokine/chemokine levels, and mitochondrial bioenergetic capacity.ResultsDimethyl fumarate treatment reversed mechanical allodynia (injury-vehicle, 0.45 ± 0.06 g [mean ± SD]; injury-dimethyl fumarate, 8.2 ± 0.16 g; P < 0.001) and hyperalgesia induced by nerve injury (injury-vehicle, 2 of 6 crossed noxious probes; injury-dimethyl fumarate, 6 of 6 crossed; P = 0.013). The antiallodynic effect of dimethyl fumarate was lost in nerve-injured Nfe2l2 mice, but retained in nerve-injured male and female wild type mice (wild type, 0.94 ± 0.25 g; Nfe2l2, 0.02 ± 0.01 g; P < 0.001). Superoxide dismutase activity was increased by dimethyl fumarate after nerve injury (injury-vehicle, 3.96 ± 1.28 mU/mg; injury-dimethyl fumarate, 7.97 ± 0.47 mU/mg; P < 0.001). Treatment reduced the injury-dependent increases in cytokines and chemokines, including interleukin-1? (injury-vehicle, 13.30 ± 2.95 pg/mg; injury-dimethyl fumarate, 6.33 ± 1.97 pg/mg; P = 0.022). Injury-impaired mitochondrial bioenergetics, including basal respiratory capacity, were restored by dimethyl fumarate treatment (P = 0.025).ConclusionsDimethyl fumarate, a nonopioid and orally-bioavailable drug, alleviated nociceptive hypersensitivity induced by peripheral nerve injury via activation of NFE2L2 antioxidant signaling. Dimethyl fumarate also resolved neuroinflammation and mitochondrial dysfunction-oxidative stress-dependent mechanisms that drive nociceptive hypersensitivity after nerve injury.