Effects of an intravenous ketamine infusion on inflammatory cytokine levels in male and female Sprague–Dawley rats

Abstract

Background Ketamine, a multimodal dissociative anesthetic drug, is widely used as an analgesic following traumatic injury. Although ketamine may produce anti-inflammatory effects when administered after injury, the immunomodulatory properties of intravenous (IV) ketamine in a non-inflammatory condition are unclear. In addition, most preclinical studies use an intraperitoneal (IP) injection of ketamine, which limits its clinical translation as patients usually receive an IV ketamine infusion after injury. Methods Here, we administered sub-anesthetic doses of a single IV ketamine infusion (0, 10, or 40 mg/kg) to male and female Sprague–Dawley rats over a 2-h period. We collected blood samples at 2- and 4-h post-ketamine infusion to determine plasma inflammatory cytokine levels using multiplex immunoassays. Results The 10 mg/kg ketamine infusion reduced spontaneous locomotor activity in male and female rats, while the 40 mg/kg infusion stimulated activity in female, but not male, rats. The IV ketamine infusion produced dose-dependent and sex-specific effects on plasma inflammatory cytokine levels. A ketamine infusion reduced KC/GRO and tumor necrosis factor alpha (TNF-α) levels in both male and female rats, interleukin-6 (IL-6) levels in female rats, and interleukin-10 (IL-10) levels in male rats. However, most cytokine levels returned to control levels at 4-h post-infusion, except for IL-6 levels in male rats and TNF-α levels in female rats, indicating a different trajectory of certain cytokine changes over time following ketamine administration. Conclusions The current findings suggest that sub-anesthetic doses of an IV ketamine infusion may produce sex-related differences in the effects on peripheral inflammatory markers in rodents, and further research is warranted to determine potential therapeutic effects of an IV ketamine infusion in an inflammatory condition.

A single dose of ketamine relieves fentanyl-induced-hyperalgesia by reducing inflammation initiated by the TLR4/NF-κB pathway in rat spinal cord neurons

“…An important point to note is that, like the TLR4 inhibitor TAK-242, a single dose of ketamine can alleviate hyperalgesia and reduce the hyperactivation of TLR4/ NF-κB induced by fentanyl. Studies have indicated that KC/GRO and TNF-α levels in male and female rats decreased 2 h after intravenous administration of ketamine, as did interleukin-6 (IL-6) levels in female rats and interleukin-10 (IL-10) levels in male rats (28). Low-dose ketamine inhibits neuroinflammation in PC12 cells by activating α7nAChR-mediated cholinergic antiinflammatory pathways, such as the TLR4/MAPK/NF-κB signaling pathway (29), which suggests that ketamine may inhibit TLR4 expression in the same way.…”

The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression

“…As with other psychiatric treatments, the exact biological mechanisms underlying ketamine’s psychiatric benefits are subject to ongoing research and debate [as described in multiple recent reviews ( 50–52 )], including the role of NMDA receptors in its antidepressive effects ( 53 ). Amongst many identified potential mechanisms, cellular and animal studies have demonstrated that ketamine can promote neuroplasticity (e.g., dendritic spinogenesis) and thereby reduce or reverse stress-related changes ( 54 , 55 ), reduce inflammation ( 56 ), and dramatically alter neural dynamics ( 57 , 58 ). Studies in humans have also found ketamine to transiently alter cerebral GABA and glutamate concentrations ( 59 , 60 ), increase neural activity in areas associated with reward processing ( 61 ), and potentially normalize default mode network connectivity abnormalities of depression ( 62 ).…”

“…As with other psychiatric treatments, the exact biological mechanisms underlying ketamine's psychiatric benefits are subject to ongoing research and debate [as described in multiple recent reviews (50)(51)(52)], including the role of NMDA receptors in its antidepressive effects (53). Amongst many identified potential mechanisms, cellular and animal studies have demonstrated that ketamine can promote neuroplasticity (e.g., dendritic spinogenesis) and thereby reduce or reverse stress-related changes (54, 55), reduce inflammation (56), and dramatically alter neural dynamics (57,58).…”

Effects of a Subanesthetic Ketamine Infusion on Inflammatory and Behavioral Outcomes after Closed Head Injury in Rats

“…Animals received a ketamine or saline infusion one hour following the CHIMERA procedure. As previously described [ 47 ], racemic (±) ketamine hydrochloride (100 mg/mL) (Covetrus, Dublin, OH, USA) was diluted in 0.9% sterile saline before the infusion. The ketamine infusion (0, 10, or 20 mg/kg, IV) took place over two hours.…”