A Polyamine-Deficient Diet Prevents Oxaliplatin-Induced Acute Cold and Mechanical Hypersensitivity in Rats

Abstract

BackgroundOxaliplatin is an anticancer drug used for the treatment of advanced colorectal cancer, but it can also cause painful peripheral neuropathies. The pathophysiology of these neuropathies has not been yet fully elucidated, but may involve spinal N-methyl-D-aspartate (NMDA) receptors, particularly the NR2B subunit. As polyamines are positive modulators of NMDA-NR2B receptors and mainly originate from dietary intake, the modulation of polyamines intake could represent an interesting way to prevent/modulate neuropathic pain symptoms by opposing glutamate neurotransmission.MethodsThe effect of a polyamine deficient diet was investigated in an animal model of oxaliplatin-induced acute pain hypersensitivity using behavioral tests (mechanical and cold hypersensitivity). The involvement of spinal glutamate neurotransmission was monitored by using a proton nuclear magnetic resonance spectroscopy based metabolomic approach and by assessing the expression and phosphorylation of the NR2B subunit of the NMDA receptor.ResultsA 7-day polyamine deficient diet totally prevented oxaliplatin-induced acute cold hypersensitivity and mechanical allodynia. Oxaliplatin-induced pain hypersensitivity was not associated with an increase in NR2B subunit expression or phosphorylation, but with an increase of glutamate level in the spinal dorsal horn which was completely prevented by a polyamine deficient diet. As a validation that the oxaliplatin-induced hypersensitivity could be due to an increased activity of the spinal glutamate system, an intrathecal administration of the specific NR2B antagonist, ifenprodil, totally reversed oxaliplatin-induced mechanical and cold hypersensitivity.ConclusionA polyamine deficient diet could represent a promising and valuable nutritional therapy to prevent oxaliplatin-induced acute pain hypersensitivity.

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats

“…At physiological pH, polyamine can positively modulate NMDAR function by inhibiting GluN1-GluN2B channel function [56; 71]. Decreasing the polyamine levels in the diet can ameliorate hyperalgesic status by decreasing glutamate levels in the spinal cord [14] and potentiate the analgesic effect of morphine [59]. Using models of hyperalgesia (inflammatory, post-incision, neuropathic, OIH, and non-nociceptive environmental stress), Rivat and colleagues showed that a polyamine-deficient diet prevented phosphorylation on tyrosine residues of the GluN2B subunit and inhibited the appearance of hyperalgesia [59].…”

Lifestyle‐Related Factors in the Self‐Management of Chemotherapy‐Induced Peripheral Neuropathy in Colorectal Cancer: A Systematic Review

“…It could therefore be relevant to further investigate acupuncture treatments, as such traditional medicine might offer patients a drug-free coping mechanism for neuropathic pain. Lastly, animal studies have provided insight into other factors/supplements which could be worth studying in CRC patients, such as curcumin, flavonoids, reduced poly-amine diets, and vitamin C, all of which have been found to decrease CIPN in mice models [64–68]. …”

Minimizing chemotherapy-induced peripheral neuropathy: preclinical and clinical development of new perspectives

“…Indeed, this polyamine-deficient diet totally prevented cold and mechanical allodynia in animal models of acute oxaliplatin-induced peripheral neuropathy. Moreover, this polyamine-deficient diet suppressed the increase of the spinal glutamate concentration found in neuropathic rats subjected to pain [80]. A clinical trial is ongoing and assessing the preventive effect of a polyamine-depleted diet on oxaliplatin-induced peripheral neuropathy (Table 5).…”