Paclitaxel-induced hyperalgesia modulates negative affective component of pain and NR1 receptor expression in the frontal cortex in rats.
Paclitaxel, one of the chemotherapeutic agents clinically used to treat several types of cancer, produces side effects such as peripheral neuropathy, sensory abnormalities, and hyperalgesia. Since hyperalgesia remains after cessation of paclitaxel therapy and becomes chronic, we hypothesize that alteration in memory and the cognitive process of pain underlies hyperalgesia. To test this hypothesis, we examined whether drug-induced hyperalgesia alters the affective component of pain and the NMDA-NR1 and mGluR1 receptors as a mediator for signal transmission and memory of pain. Mechanical sensitivity was measured by von Frey filament test after intraperitoneal injection of paclitaxel in rats. Paclitaxel-induced hyperalgesia was confirmed over almost the entire 14-day period of observation after the treatment. The effect of paclitaxel-induced hyperalgesia on the affective component of pain was assessed using pain-induced place aversion. The formalin-induced conditioned place aversion was completely abolished in the paclitaxel-treated rats. Immunoblot analysis of NR1 and mGluR1 protein levels in various brain regions was performed after paclitaxel treatment. Treatment reduced only the NR1 expression within the frontal cortex. These results suggest that the hypofunction of memory processes with the reduced NMDA receptors in the frontal cortex might be involved in the expression of abnormal emotional behaviors accompanied by hyperalgesia.
Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan. Electronic address: noda1219@ahs.kitasato-u.ac.jp.
Kazuko
K
Noda
Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan; Division of Brain Science, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan. Electronic address: akita310@ahs.kitasato-u.ac.jp.
Hisanao
H
Akita
Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan. Electronic address: masa422@ahs.kitasato-u.ac.jp.
Masanori
M
Ogata
Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan; Division of Brain Science, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan. Electronic address: sajim@ahs.kitasato-u.ac.jp.
Makoto
M
Saji
D000704:Analysis of Variance; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D003216:Conditioning, Operant / Q000187:drug effects; D005557:Formaldehyde / Q000009:adverse effects; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000633:toxicity*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde; D017239:Paclitaxel
Conditioned place aversion; Emotion; Hyperalgesia; NR1 receptor; Paclitaxel