Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice
Introduction
Pain has been described as a multi-dimensional state composed of sensory, affective, and cognitive components (Apkarian et al., 2004, Ji et al., 2010, Neugebauer et al., 2009). Furthermore, pain states that require clinical intervention are often accompanied by changes in affective behaviors (Hummel et al., 2008, Joshi and Honore, 2006, Mogil, 2009, Whiteside et al., 2013). Thus, animal models that measure pain-related changes in affective behaviors may serve as important tools in the development of more efficacious analgesic drugs. Recent behavioral studies suggest that these affective components of pain can be evaluated in rodents. For example, depression of positively reinforced operant responding maintained by delivery of food (Martin et al., 2004) or electrical brain stimulation (Do Carmo et al., 2009, Leitl et al., 2014) was reported after injury or treatment with experimental noxious stimuli. In addition, recent studies in rats showed that a aversion to a noxious stimuli can also be assessed with a conditioned place aversion (CPA) test after intraperitoneal (i.p.) injection of acetic acid (AA) (Deyama et al., 2010) or intraplantar injection of complete Freund's adjuvant (Johansen et al., 2001, Zhang et al., 2013). These studies revealed that several limbic brain areas, such as the anterior cingulate cortex (Deyama et al., 2007, Johansen and Fields, 2004, Johansen et al., 2001), central amygdala (Deyama et al., 2010), and bed nucleus of the stria terminalis (Deyama et al., 2008, Deyama et al., 2007), mediate this CPA. There has been limited studies exploring the induction of CPA after noxious stimulus delivery in mice (Browne and Woolf, 2014, Daou et al., 2013), but such studies might be useful given the molecular and genetic applicability of mouse models to human disease phenotypes (Rosenthal and Brown, 2007).
Toward that end, the purpose of this study was to evaluate the expression and pharmacological modulation of CPA produced in mice by a commonly used acute visceral noxious stimulus (i.p. AA). We hypothesized that AA would induce place aversion, and that AA-induced CPA would be sensitive to blockade by pretreatment with two clinically effective analgesics, the nonsteroidal anti-inflammatory drug ketoprofen or the mu opioid receptor agonist morphine. Effects of the kappa opioid receptor agonist U50,488H and the kappa antagonist JDTic were also evaluated. Kappa agonists that readily cross the blood–brain barrier to produce centrally mediated effects after systemic administration constitute one class of drugs that produces antinociception in many conventional preclinical assays of pain (Broadbear et al., 1994, Horan et al., 1991); however, centrally acting kappa agonists have failed to meet safety and efficacy criteria for clinical use (Pande et al., 1996a, Pande et al., 1996b). Consequently, kappa agonists exemplify the potential for “false positive” outcomes in conventional preclinical assays of candidate analgesics (Mogil, 2009, Negus et al., 2006, Vierck et al., 2008, Whiteside et al., 2013), and U50,488H was tested here as a negative control. We hypothesized that U50,488H would fail to block AA-induced CPA. Conversely, it has been suggested that negative affective components of pain may involve activation of endogenous kappa opioid systems in limbic brain regions (Cahill et al., 2014). This hypothesis predicts that AA-induced CPA might be blocked by a kappa antagonist like JDTic.
The present study also included two other components. First, the expression and pharmacological modulation of AA-induced CPA were compared to the expression and pharmacological modulation of the AA-induced stretching response. The stretching (or “writhing”) response is a commonly used behavioral endpoint in studies of visceral pain elicited by i.p. injection of AA or other chemical irritants (Koster et al., 1959). However, we have categorized the stretching response as an example of a “pain-stimulated behavior,” which can be defined as a behavior that increases in rate, frequency or intensity after delivery of a noxious stimulus (Negus et al., 2010, Negus et al., 2006). Exclusive reliance on pain-stimulated behaviors in preclinical research can be problematic because they are sensitive not only to treatments that reduce sensory sensitivity to the noxious stimulus, but also to treatments that produce motor impairment. We hypothesized that AA-induced stretching would be blocked by ketoprofen, morphine and U50,488H but not by JDTic. Second, ketoprofen and morphine effects on AA-induced CPA were compared to their effects on CPA induced by lithium chloride (LiCl), a non-noxious aversive stimulus (Lett, 1985). Insofar as LiCl-induced aversion is not thought to involve nociception, we hypothesized that neither ketoprofen nor morphine would block LiCl-induced aversion.
Section snippets
Animals
Male adult ICR mice (20–25 g) obtained from Harlan Laboratories (Indianapolis, IN) were used throughout the study. Animals were housed in an AAALAC approved facility in groups of four and had free access to food and water. Experiments were performed during the light cycle and were approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University.
Drugs
U50,488H [trans- (±) −3,4-Dichloro-N-methyl-N-[2- (1-pyrrolidinyl) cyclohexyl] benzeneacetamide methanesulfonate salt],
Acetic acid-induced stimulation of stretching and conditioned place aversion
AA produced a concentration-dependent increase in stretching. Sterile water (acid vehicle) did not elicit stretching behavior. One-way ANOVA indicated that the number of stretches following 0.32, 0.56 and 1% AA was significantly greater than the number of stretches following i.p. water [F(3,20) = 44.04; p < 0.001] (Fig. 1A) with an ED50 value of 0.54 (0.46–0.62) mg/kg. AA also produced concentration-dependent CPA [F(3,26) = 21.5; p < 0.001] (Fig. 1C) with an ED50 value of 0.64 (0.54–0.76)
Discussion
Since pain is an unpleasant sensory and emotional experience, it is important to evaluate the negative affective component of pain as well as measuring the nociceptive behaviors. The purpose of the present paper was to develop and characterize a mouse model evaluating drug effects on an aversive behavior induced by a noxious stimulus. Our main findings were that i.p. injection of AA induced in the mouse an aversive behavior as measured in the CPA test in a dose- and time-dependent manner. In
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgement
This work was supported by NIH grants R01DA-019377 (MID), R01NS070715 (SSN), and R01DA030404 (SSN).
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Contributed equally to the manuscript.