Jo Ohta1, Takashi Suto2, Daiki Kato3, Tadanao Hiroki4, Hideaki Obata5, Shigeru Saito6. 1. Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. Electronic address: gunmaneth6349@gunma-u.ac.jp. 2. Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. Electronic address: takashisuto@gunma-u.ac.jp. 3. Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. Electronic address: m1600b01@gunma-u.ac.jp. 4. Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. Electronic address: t-hiroki@gunma-u.ac.jp. 5. Department of Anesthesiology and Center for Pain Management, Fukushima Medical University, 1 Hikariga-oka, Fukushima, Fukushima 960-1295, Japan. Electronic address: obata@fmu.ac.jp. 6. Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. Electronic address: shigerus@gunma-u.ac.jp.
Abstract
BACKGROUND: Preoperative pain and impaired endogenous analgesia are risk factors of chronic postsurgical persistent pain (CPSP). A Chronic neuropathic pain model induced by spinal nerve ligation (SNL6W) shows impaired endogenous analgesia and delayed recovery from incisional pain. Repeated amitriptyline treatment can restore the endogenous analgesia, but its effects on delayed recovery are not clear. METHODS: A plantar incision was made on the side contralateral to the nerve ligation in SNL6W rats. Withdrawal thresholds were measured by von Frey filament test until 28 d after surgery. Amitriptyline (10 mg·kg-1·d-1) or vehicle was administered for 13 d perioperatively. To examine the roles of noradrenergic and cholinergic signals in the spinal dorsal horn, pharmacological antagonism, measurement of each neurotransmitter concentration, and immunohistochemistry were conducted. RESULTS: Recovery of the withdrawal threshold of SNL6W animals to pre-incision values required 28 d after surgery, while naive animals recovered within 14 d. Intrathecal injection of alpha2 adrenoceptor antagonist (idazoxan) or muscarinic cholinergic receptor antagonist (atropine) decreased the withdrawal threshold on POD14 and 21 in naive animals, but not in SNL6W rats. Repeated amitriptyline treatment attenuated the delayed recovery in SNL6W rats, and the effect was antagonized by muscarinic cholinergic receptor antagonist. Beside the concentration of acetylcholine and its synthetic enzyme were not altered by the treatment. CONCLUSIONS: Noradrenergic and cholinergic analgesia, which is necessary for normal recovery, is lost in the SNL6W rats. A strategy to enhance endogenous analgesia using antidepressants, rather than simple analgesia, may help to prevent CPSP in chronic pain patients.
BACKGROUND: Preoperative pain and impaired endogenous analgesia are risk factors of chronic postsurgical persistent pain (CPSP). A Chronic neuropathic pain model induced by spinal nerve ligation (SNL6W) shows impaired endogenous analgesia and delayed recovery from incisional pain. Repeated amitriptyline treatment can restore the endogenous analgesia, but its effects on delayed recovery are not clear. METHODS: A plantar incision was made on the side contralateral to the nerve ligation in SNL6W rats. Withdrawal thresholds were measured by von Frey filament test until 28 d after surgery. Amitriptyline (10 mg·kg-1·d-1) or vehicle was administered for 13 d perioperatively. To examine the roles of noradrenergic and cholinergic signals in the spinal dorsal horn, pharmacological antagonism, measurement of each neurotransmitter concentration, and immunohistochemistry were conducted. RESULTS: Recovery of the withdrawal threshold of SNL6W animals to pre-incision values required 28 d after surgery, while naive animals recovered within 14 d. Intrathecal injection of alpha2 adrenoceptor antagonist (idazoxan) or muscarinic cholinergic receptor antagonist (atropine) decreased the withdrawal threshold on POD14 and 21 in naive animals, but not in SNL6W rats. Repeated amitriptyline treatment attenuated the delayed recovery in SNL6W rats, and the effect was antagonized by muscarinic cholinergic receptor antagonist. Beside the concentration of acetylcholine and its synthetic enzyme were not altered by the treatment. CONCLUSIONS: Noradrenergic and cholinergic analgesia, which is necessary for normal recovery, is lost in the SNL6W rats. A strategy to enhance endogenous analgesia using antidepressants, rather than simple analgesia, may help to prevent CPSP in chronic painpatients.