Antagonism of orexin-1 receptors attenuates swim- and restraint stress-induced antinociceptive behaviors in formalin test

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Abstract

Orexin (ORX) plays an important role in pain modulation. ORX receptors have been found in many brain structures and are known to be involved in pain processing. It is well-established that the acute and chronic forms of stress could induce hormonal and neuronal changes that affect both pain threshold and nociceptive behaviors. The role of OX1R receptors in stress-induced analgesia (SIA) has not been fully elucidated. In the present study, using the formalin test, attempts were made to evaluate the effects of acute immobilization restraint stress and swimming stress on pain behavioral responses following OX1R antagonist administration in rats. Animals received OX1R antagonist (SB-334867), vehicle, or naloxone before exposure to acute restraint stress (30 min) or swimming stress test (6 min, 20 ± 1 °C), and immediately submitted to hind paw formalin injection (50 μl, 2%). Acute 30-min exposure to restraint stress as well as 6-min exposure to swim stress could significantly reduce the formalin-induced nociceptive behaviors in rats. This antinociceptive effect with either restraint stress or swim stress was fully prevented by OX1R antagonist (SB-334867), while the SB-334867 alone had no effect. However, the opioid receptor antagonist naloxone could not totally reverse the antinociception effect with either form of stress. It is suggested that OX1R might be involved in antinociception behaviors induced by these two forms of stress. These data highlight the significant role of OX1R as a novel target for treatment of stress-related disorders.

Highlights

► Acute exposure to swim stress reduced formalin-induced nociceptive behaviors. ► Acute exposure to restraint stress reduced formalin-induced nociceptive behaviors. ► Blocking the orexin-1 receptors decreased stress-induced antinociceptive behaviors. ► Naloxone partially decreased the stress induced antinociceptive behaviors.

Introduction

Stress is shown to activate multiple neural and neurotransmitter systems involved in suppression of pain sensation (Madden et al., 1977, Guillemin et al., 1977, Bodnar et al., 1980a). This phenomenon, known as stress-induced analgesia (SIA), is activated by endogenous pain inhibitory systems (Madden et al., 1977, Guillemin et al., 1977, Bodnar et al., 1980a). Regarding the stress, the opioid and non-opioid forms of SIA have been elicited in rodents (Madden et al., 1977, Bodnar et al., 1980a). Acute stress initiates a cascade of neuronal and hormonal changes and induces analgesia in animals and humans (Amit and Galina, 1986, Ford and Finn, 2008). It has been reported that blocking the endogenous opioid system with naloxone or naltrexone attenuates the nociceptive behavioral responses following exposure to stress, indicating that the endogenous opioid system is involved in SIA (Amit and Galina, 1986). Systemic or intracerebroventricular (i.c.v.) injection of μ-, κ-, or δ-opioid receptor antagonists is demonstrated to prevent the SIA or fear-conditioned analgesia in rat (Akil et al., 1986, Fanselow et al., 1989, Butler and Finn, 2009).

Stress was shown to affect the brain activity and promote the long-term changes in multiple neural systems (McEwen, 2000, Imbe et al., 2004). Considering the features of stressor (such as duration, intensity, and temporal aspects of the same stressor) applied, the nature of analgesic response might be different (Watkins and Mayer, 1986, Amit and Galina, 1986). In some stressful situations, the blockade of endogenous opioid system is reported to lack the potential to completely reverse the SIA and this supports the idea that the activation of endogenous neurotransmitters and neuropeptides, as non-opioid mechanisms, may be involved in SIA (Lewis et al., 1980, Watkins and Mayer, 1982). There are evidences that OX1R is involved in responsiveness to both pain and stressful stimuli and, therefore, it may be involved in SIA (Watanabe et al., 2005, Sofi-Abadi et al., 2011). For example, ORX knockout mice were reported to present greater degree of hyperalgesia and lower SIA caused by peripheral inflammation than that observed in wild type mice (Watanabe et al., 2005). It has been shown that administration of orexin-A (ORXA) produces naloxone-insensitive analgesic effects by acting on spinal and/or supraspinal OX1R (Jeong and Holden, 2009). Also, it is documented that the intrathecal administration of ORXA inhibits pain perception in behavioral tests (Bingham et al., 2001, Yamamoto et al., 2002).

Furthermore, the data from a previously published study have confirmed that ORXA administration produces the analgesic effects in the hotplate, tail-flick, and formalin tests in mice, although these effects were not reversed by naloxone (Mobarakeh et al., 2005). Therefore, it was hypothesized that ORX possibly mediates the non-opioid SIA through OX1R activation. The present study was designed to investigate the possible role of OX1R on stress-induced antinociception. In this study, attempts were made to examine the effect of ICV injection of OX1R antagonist (SB-334867) on behavioral manifestations of animal pain during formalin test in rat as an animal model of tonic pain after acute exposure to either restraint or swim stress.

Section snippets

Subjects

Adult Sprague–Dawley rats (220–300 g) were purchased from Razi institute (Karaj, Iran). Animals were housed in groups of three rats per cage at temperature controlled room, under a 12 h light–dark cycle with lights on from 7:00 to 19:00. Food and water were provided. All experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80-23, revised 1996) and were approved by the Research and Ethics Committee of

Effects of OX1R antagonist (SB-334867) on antinociceptive behaviors caused by acute restraint stress and swim stress in formalin test

To evaluate the effect of SB-334867 and naloxone alone on formalin test, we injected the drug or vehicle alone and followed by hind paw formalin injection. Pretreatment with SB-334867 (0.1 mM) or naloxone (3 mg/kg) failed to produce significant effect on formalin induced nociceptive behaviors (Fig. 1).

To evaluate the effect of restraint stress and swim stress on nociceptive response in formalin test, we used either of the stress protocols. Formalin scores were measured at 3-min intervals during 60

Discussion

We demonstrated that (a) antinociceptive effects of stress were significantly reduced by a prior microinjection of SB-334867 in formalin test and (b) the opioid system partially affected the antinociception, induced by stress in both models. Stress activates multiple neural systems that suppress pain sensation. This phenomenon known as SIA is activated by endogenous pain inhibitory systems (Spiaggia et al., 1979, Bodnar et al., 1980b). Several studies have shown that stress, through top-down

Conflict of interest

The authors report no financial or other conflicts of interest relevant to the subject of this article.

Acknowledgments

This research was supported by a grant from Qazvin University of Medical Sciences, Qazvin, Iran and Iran National Science Foundation (INSF). The authors wish to express their appreciation to Elmira Ghasemi and Asghar Parvishan for their assistance and support. We also thank Dr Ali A Pahlevan for his meticulous work on revision of the final English version of the manuscript.

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