Topical combination of meldonium and N‐acetyl cysteine relieves allodynia in rat models of CRPS‐1 and peripheral neuropathic pain by enhancing NO‐mediated tissue oxygenation

Abstract

Local microvascular dysfunction and consequent tissue ischemia/hypoxia contribute to the symptoms of complex regional pain syndrome (CRPS) and peripheral neuropathic pain. As nitric oxide (NO) is a key regulator of microvascular blood flow, compounds that increase it are potentially therapeutic for these pain conditions. This led us to hypothesize that the topical administration of drugs that modulate local tissue NO levels can alleviate the pain of CRPS and peripheral neuropathic pain. We investigated the anti‐allodynic effect of a combination of two NO‐modulating drugs: meldonium and N‐acetylcysteine (NAC). An equimolar topical formulation of the two drugs was tested on chronic post‐ischemic pain (CPIP), a rat model of CRPS, as well as chronic constriction injury (CCI) of the sciatic nerve and chemotherapy‐induced painful neuropathy (CIPN), rat models of peripheral neuropathic pain. Topical meldonium‐NAC produced significant anti‐allodynia in CPIP, CCI, and CIPN rats. Moreover repeated application of topical meldonium‐NAC produced an increase in the duration of anti‐allodynia in the CPIP and CCI rats. While pre‐treatment with an NO synthase inhibitor attenuated the anti‐allodynic effects of meldonium‐NAC, 30‐min hyperbaric oxygen treatment combined with a non‐effective dose of meldonium‐NAC produced significant anti‐allodynic effects in CPIP rats. Both experiments implicated NO in the drug combination's anti‐allodynic effects. To ascertain the role played by changes in local tissue NO, we performed a quantification of plantar muscle NO in CPIP rats after hind paw topical treatment with meldonium‐NAC and revealed significantly increased plantar muscle NO levels in drug‐treated rats. The drug combination also reversed the reduction in tissue oxygenation normally observed in CPIP hind paws. In addition to introducing a novel topical treatment for mechanical allodynia in CRPS and peripheral neuropathic pain, this work showcases the analgesic potential of locally targeting microvascular dysfunction and tissue ischemia/hypoxia in these conditions, with emphasis on the role of NO.

Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation

“…Tissue inflammation and oxidative injury are considered important contributing factors to CRPS-I pathogenesis [49]. Antioxidants have shown pain-relieving effects on animal models of CRPS-I [7,50,51]. However, studies that systematically evaluated oxidative stress status in CRPS-I are still lacking.…”

Rosiglitazone Alleviates Mechanical Allodynia of Rats with Bone Cancer Pain through the Activation of PPAR-γ to Inhibit the NF-κB/NLRP3 Inflammatory Axis in Spinal Cord Neurons

“…During the operation, a heating blanket was used to keep the body temperature stable, and all operators skillfully performed the related surgical procedures to shorten the operation time. With reference to previous studies [ 29 , 30 ], sodium pentobarbital was prepared as a solution with a final concentration of 5 mg/ml to avoid irritation. After surgery, wounds were topically disinfected with 75% ( v / v ) ethanol, but not with systemic antibiotics, to avoid interference with experimental pharmacological treatments.…”

Spinal Nrf2 translocation may inhibit neuronal NF‐κB activation and alleviate allodynia in a rat model of bone cancer pain

“…bone cancer pain, HO-1, neuroinflammation, NF-κB, Nrf2, nuclear translocation chose the best experimental scheme and reduced the number of animals as much as possible. Referring to the previous literature (Fulas et al, 2020;Hu et al, 2017;Ma et al, 2020), sodium pentobarbital was used to anaesthetize rats. Sodium pentobarbital was finally configured to a final concentration of 5 mg/ml solution to avoid irritation.…”