Nifedipine potentiates antinociceptive effects of morphine in rats by decreasing hypothalamic pituitary adrenal axis activity Saeed Esmaeili Mahani a,b , Sohyla Vahedi c , Fereshteh Motamedi a , Aliasghar Pourshanazari c , Mohammad Khaksari c , Abolhasan Ahmadiani a, * a Department of Physiology & Pharmacology, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, P.O. Box: 19835-355, Tehran, Iran b Department of Biology, Faculty of Sciences, Shahid Bahonar University, Kerman, Iran c Department of Physiology, Faculty of Medical Sciences, Kerman & Rafsanjan, Iran Received 25 April 2005; received in revised form 30 June 2005; accepted 7 July 2005 Available online 19 August 2005 Abstract It has been shown that nifedipine, as a calcium channel blocker can potentiate the antinociceptive effect of morphine; however, the role of Hypothalamic – Pituitary –Adrenal (HPA) axis on this action has not been elucidated. We examined the effect of nifedipine on morphine- induced analgesia in intact and adrenalectomized (ADX) rats and on HPA activity induced by morphine. To determine the effect of nifedipine on morphine analgesia, nifedipine (2 mg/kg i.p.) that had no antinociceptive effect, was injected concomitant with sub-effective dose of morphine (1 and 2 mg/kg). The tail-flick test was used to assess the nociceptive threshold, before and 15, 30, 60, 90, 120 and 180 min after drug administration. Our results showed that, nifedipine could potentiate the antinociceptive effect of morphine and this effect of nifedipine in ADX was greater than sham operated rats which, was reversed by corticosterone replacement. Nifedipine has an inhibitory effect on morphine -induced corticosterone secretion. Thus, the data indicate that the mechanism underlying the potentiation of morphine analgesia by nifedipine involves mediation, at least in part, by attenuating the effect of morphine on HPA axis. D 2005 Elsevier Inc. All rights reserved. Keywords: Morphine; Analgesia; Nifedipine; HPA axis; Corticosterone 1. Introduction Opioids have been used for treating moderate to severe pain. Activation of opioid receptor inhibits adenylyl cyclase activity via inhibitory G-proteins, inhibits voltage activated calcium channels, reducing the Ca ++ influx, thus inhibits neurotransmitter release and attenuates pain sensa- tion (Childers, 1991). Due to the fact that calcium influx is essential for normal sensory processing, inhibition of Ca ++ movement would contribute to antinociception (Schmidt et al., 1980; Venegas and Schaible, 2000; Todorovic et al., 2002; Heinke et al., 2004; Galeotti et al., 2004). Not surprisingly, Ca ++ channel antagonists have been shown to induce antinociceptive effect (Del Pozo et al., 1990; Miranda et al., 1993; Weizman et al., 1999; Todorovic et al., 2004; Chen et al., 2005). Many investigators reported that calcium channel blockers potentiate the analgesic effect of morphine (Hoffmeister and Tettenborn, 1986; Contreras et al., 1988; Antkiewicz-Michaluk et al., 1993; Santilan et al., 1994; Michaluk et al., 1998; Assi, 2001; Dogrul et al., 2001; Maeda et al., 2002; Fukuizumi et al., 2003; Yokoyama et al., 2004; Shimizu et al., 2004a,b). In many in vitro studies, it has been demonstrated that glucocorticoids can potentiate Ca ++ influx and accelerate the release of Ca ++ from intracellular stores, and cortico- sterone can increase Ca ++ entry through the high voltage activated (L-type) calcium channel (Nair et al., 1998; Zhou et al., 2000; Kole et al., 2001; Karast et al., 2002; 0091-3057/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2005.07.006 * Corresponding author. Tel./fax: +98 21 2403154. E-mail address: aahmadiani@yahoo.com (A. Ahmadiani). Pharmacology, Biochemistry and Behavior 82 (2005) 17 – 23 www.elsevier.com/locate/pharmbiochembeh