Negative reinforcement reveals spontaneous pain in mice with tissue and nerve injury

Abstract

Spontaneous ongoing pain is a major clinic complaint of patients suffered with chronic pain. Understanding the mechanisms underlying this non-evoked pain is hindered by limited approaches of measurement in animals. Recently, conditioned place preference (CPP) has been proposed to evaluate spontaneous pain in rats. Given the existence of numerous transgenic mouse models, an obvious question is if this measurement of spontaneous pain can be applied to studies in mice. Here we present evidence from several models of mouse chronic pain. First, persistent inflammatory pain was generated in mice by intraplantar injection of complete Freund's adjuvant (CFA). The possible presence of CFA-induced ongoing pain was then determined using CPP to lidocaine or clonidine, two non-rewarding analgesic drugs. Intrathecal (i.t.) injection of lidocaine or clonidine rapidly blocked CFA-induced thermal hyperalgesia and mechanical allodynia, indicating the effective pain relief by these drugs. CFA mice elicited a robust preference for the lidocaine or clonidine paired chamber after single-trial conditioning on post-CFA day 1. In contrast, these drugs did not produce place preference in naive mice. In the second set of studies, nerve injury-induced sensory sensitivity was produced by the ligation of spinal nerves L5/L6 (SNL). Thermal and mechanical hypersensitivity was observed within 2 days and lasted for at least 21 days following SNL. Both lidocaine and clonidine elicited significant CPP to the drug-paired chambers. As a proof-of-concept, we further demonstrated that Berkeley sickle cell transgenic mice exhibited signs of spontaneous pain by CPP to these drugs, without the need of treatment with CFA or surgery injury to peripheral nerves. Taken together, these data suggested CPP as a powerful instrument to investigate spontaneous pain in mice. Supported in part by the NIH grant R01HL098141. Spontaneous ongoing pain is a major clinic complaint of patients suffered with chronic pain. Understanding the mechanisms underlying this non-evoked pain is hindered by limited approaches of measurement in animals. Recently, conditioned place preference (CPP) has been proposed to evaluate spontaneous pain in rats. Given the existence of numerous transgenic mouse models, an obvious question is if this measurement of spontaneous pain can be applied to studies in mice. Here we present evidence from several models of mouse chronic pain. First, persistent inflammatory pain was generated in mice by intraplantar injection of complete Freund's adjuvant (CFA). The possible presence of CFA-induced ongoing pain was then determined using CPP to lidocaine or clonidine, two non-rewarding analgesic drugs. Intrathecal (i.t.) injection of lidocaine or clonidine rapidly blocked CFA-induced thermal hyperalgesia and mechanical allodynia, indicating the effective pain relief by these drugs. CFA mice elicited a robust preference for the lidocaine or clonidine paired chamber after single-trial conditioning on post-CFA day 1. In contrast, these drugs did not produce place preference in naive mice. In the second set of studies, nerve injury-induced sensory sensitivity was produced by the ligation of spinal nerves L5/L6 (SNL). Thermal and mechanical hypersensitivity was observed within 2 days and lasted for at least 21 days following SNL. Both lidocaine and clonidine elicited significant CPP to the drug-paired chambers. As a proof-of-concept, we further demonstrated that Berkeley sickle cell transgenic mice exhibited signs of spontaneous pain by CPP to these drugs, without the need of treatment with CFA or surgery injury to peripheral nerves. Taken together, these data suggested CPP as a powerful instrument to investigate spontaneous pain in mice. Supported in part by the NIH grant R01HL098141.