Minocycline alleviates nociceptive response through modulating the expression of NR2B subunit of NMDA receptor in spinal cord of rat model of painful diabetic neuropathy

Abstract

Background It has been reported that neuropathic pain can be overcome by targeting the NR2B subunit of N-methyl-Daspartate receptors (NR2B). This study aimed to investigate the effects of minocycline on phosphorylated and total expression of NR2B in the spinal cord of rats with diabetic neuropathic pain. Methods A total of 32 Sprague-Dawley male rats were randomly assigned into four groups (n = 8); control healthy, control diabetic (PDN), and PDN rats that received 80 µg or 160 µg intrathecal minocycline respectively. The rats were induced to develop diabetes and allowed to develop into the early phase of PDN for two weeks. Hot-plate and formalin tests were conducted. Intrathecal treatment of minocycline or normal saline was conducted for 7 days. The rats were sacrificed to obtain the lumbar enlargement region of the spinal cord (L4-L5) for immunohistochemistry and western blot analyses to determine the expression of phosphorylated (pNR2B) and total NR2B (NR2B). Results PDN rats showed enhanced flinching (phase 1: p < 0.001, early phase 2: p < 0.001, and late phase 2: p < 0.05) and licking responses (phase 1: p < 0.001 and early phase 2: p < 0.05). PDN rats were also associated with higher spinal expressions of pNR2B and NR2B (p < 0.001) but no significant effect on thermal hyperalgesia. Minocycline inhibited formalininduced flinching and licking responses (phase 1: p < 0.001, early phase 2: p < 0.001, and late phase 2: p < 0.05) in PDN rats with lowered spinal expressions of pNR2B (p < 0.01) and NR2B (p < 0.001) in a dose-dependent manner. Conclusion Minocycline alleviates nociceptive responses in PDN rats, possibly via suppression of NR2B activation. Therefore, minocycline could be one of the potential therapeutic antinociceptive drugs for the management of neuropathic pain.

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“…Patients' reactions to various pharmacological and non-pharmacological treatments (in terms of type and dose) are extremely varied. A crucial component in this variance could be how the pain message is transformed in the CNS 46,47 . As it ascends from its entry port (the dorsal horn), travels through the CNS, and reaches the cerebral cortex, the pain signal can be amplified or diminished (the area crucial for consciousness).…”

Antimicrobial therapies for chronic pain (part 1): analgesic mechanisms

“…Minocycline inhibits central [ 98 – 101 ] and peripheral [ 102 , 103 ] glial cell activity and attenuates the release of pro-inflammatory cytokines such as IL-1β [ 104 , 105 ] and TNF [ 106 ]. There is limited data suggesting that minocycline might also confer analgesia by binding to the NR2B subunit of N-methyl-D-aspartate (NMDA) receptors [ 107 ]. Because minocycline crosses the blood-brain barrier, recent focus has been on its potential neuroprotective effects [ 108 , 109 ], but clinical efficacy for this indication remains uncertain [ 110 ].…”

“…Numerous murine studies have demonstrated analgesic benefit in a variety of mechanistic pain categories, including neuropathic pain ( e.g ., mechanical allodynia and hyperalgesia [ 105 , 111 , 112 ], chemotherapy-induced peripheral neuropathy [CIPN] [ 113 , 114 ], and painful diabetic neuropathy [ 107 , 115 – 117 ]), nociceptive pain [ 96 , 97 , 118 , 119 ] (including visceral pain [ 120 – 122 ]), and mixed pain conditions ( e.g ., endotoxin-induced hyperalgesia and arthralgia [ 123 ], and cancer-associated bone pain [ 124 , 125 ]). Minocycline potentially improves affective components of pain, such as depression, anxiety, and fear [ 126 – 128 ], and older studies suggested that minocycline might also prevent the development of opioid tolerance via glutaminergic or anti-microglial mechanisms [ 129 , 130 ].…”