Corticotropin-releasing hormone (CRH) produces analgesia in a thermal injury model independent of its effect on systemic beta-endorphin and corticosterone M. Soledad Cepeda a , Iwona Bonney b, * , Jairo Moyano a , Daniel B. Carr b a Department of Anesthesia, San Ignacio Hospital, Javeriana University School of Medicine, Bogota, Colombia b Departments of Anesthesia and Medicine, Tufts-New England Medical Center, Box # 298, 750 Washington Street, Boston, MA 02111, USA Received 15 April 2003; received in revised form 7 October 2003; accepted 14 October 2003 Abstract To determine separately the effect of corticotropin-releasing hormone (CRH) on analgesia and on inflammation, rats were assigned to receive CRH 60 Ag/kg, CRH 300 Ag/kg, morphine 4 mg/kg, or normal saline intravenously 15 min before a burn injury. Two mesh chambers that allowed collection of fluid had been previously implanted subdermally in each rat. The skin overlying the right chamber was subject to thermal injury. The left chamber served as a control. We assessed systemic analgesia, and levels of beta-endorphin and corticosterone in plasma and in chamber fluid before, 1, 4 and 24 h after drug administration. The CRH groups exhibited longer tail flick latencies than the control group ( P = 0.0001) although the increase in latency was of smaller magnitude than in the morphine group. We did not observe a CRH dose response for analgesia. Plasma corticosterone levels were higher in the CRH 300 Ag/kg group than in the normal saline group at 4 h ( P = 0.03). Levels of beta-endorphin in plasma as well as the levels of corticosterone and beta-endorphin in chambers were similar in the CRH 300 Ag/kg group and in the normal saline group (all P values>0.1). Thus, systemically administered CRH produces analgesia in thermal injury independent of its effect on these two markers of local or systemic inflammation. D 2003 Elsevier B.V. All rights reserved. Keywords: Burn model; Opioids; Stress 1. Introduction Corticotropin-releasing hormone (CRH) is a peptide in- volved in the activation of the hypothalamic–pituitary adre- nal axis. It is released by the hypothalamus and stimulates the anterior pituitary cortex to release adrenocorticotropic hor- mone, which then activates the adrenal gland to release corticosteroids [1]. CRH plays a pivotal effect in the stress response of an organism and it also has the potential to modulate pain transmission in part by its effect on the release of beta-endorphin from the pituitary [2]. However, there is conflicting evidence on the analgesic effect of CRH [3], some studies reporting analgesia and others a lack of thereof [2]. CRH is not only present in the central nervous system, it is also present in cells of the immune system. Consequently, CRH may have an immunomodulatory role. However, studies of the actions of CRH upon inflammation have yielded conflicting results that range from an anti-inflam- matory effect to a pro-inflammatory effect [3,4]. The CRH immunomodulatory effect could affect noci- ceptive input and, therefore, might confound evaluation of its analgesic effect if both actions are evaluated at the same site [2]. Many of the studies that evaluate CRH analgesia have assessed it with in vivo tests that are sensitive to inflamma- tion (e.g., evaluation of paw pressure threshold in animals with an inflamed paw). As a result, the analgesic effect cannot be easily differentiated from the anti-inflammatory effect. The aim of the present study was to evaluate sepa- rately the analgesic and inflammatory effects of CRH. To accomplish this goal we used a burn injury model [5]. This model employs two mesh chambers implanted subcutane- ously in the dorsum of the rat. Skin overlying one of the chambers is subject to thermal injury while the other serves as a non-burn control. Inflammatory fluid accumulates in each chamber, from which it may be removed and assayed for mediators of inflammation [6]. Systemic analgesia is 0167-0115/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2003.10.027 * Corresponding author. Tel.: +1-617-636-9710, +1-617-636-9322; fax: +1-617-636-9709. E-mail address: IBonney@tufts-nemc.org (I. Bonney). www.elsevier.com/locate/regpep Regulatory Peptides 118 (2004) 39 – 43