Elsevier

Neuropharmacology

Volume 102, March 2016, Pages 236-243
Neuropharmacology

Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice

https://doi.org/10.1016/j.neuropharm.2015.11.024Get rights and content

Highlights

  • Acetic acid (AA) induced stretching and conditioned place aversion (CPA).

  • AA-stretching was blocked by ketoprofen, morphine and U50,488H but not by JDTic.

  • AA-CPA was blocked by ketoprofen, morphine but not by U50,488H and JDTic.

  • Neither ketoprofen nor morphine blocked LiCl-induced aversion.

Abstract

Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the brain and periphery. It is therefore important to develop animal models to reflect the non-reflexive assays in pain. In this study, we compared effects of the mu opioid receptor agonist morphine, the nonsteroidal anti-inflammatory drug ketoprofen and the kappa receptor opioid agonist U50,488H and antagonist JDTic on acetic acid-induced stretching and acetic acid-induced aversion in the condition place aversion (CPA) test in male ICR mice. Intraperitoneal administration of acetic acid (0.32–1%) was equipotent in stimulating stretching and CPA. Ketoprofen, morphine and U50,488H all inhibited the acid-induced stretching. Ketoprofen and morphine also blocked the acid-induced CPA but U50,488H failed to do so. The reversal ability of ketoprofen and morphine on acid-induced CPA is unique to pain-stimulated place aversion since these drugs failed to reduce non-noxious LiCl-induced CPA. Overall, this study characterized and validated a preclinical mouse model of pain-related aversive behavior that can be used to assess genetic and biological mechanisms of pain as well as improving the predictive validity of preclinical studies on candidate analgesics.

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).

References (45)

  • R.L. Papke et al.

    The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor

    Neuropharmacology

    (2015)
  • L. Rinaman et al.

    Ondansetron blocks LiCl-induced conditioned place avoidance but not conditioned taste/flavor avoidance in rats

    Physiol. Behav.

    (2009)
  • G.W. Stevenson et al.

    Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia: effects of morphine on acetic acid-suppressed feeding in C57BL/6J mice

    J. Pain

    (2006)
  • G.W. Stevenson et al.

    Targeting pain-depressed behaviors in preclinical assays of pain and analgesia: drug effects on acetic acid-depressed locomotor activity in ICR mice

    Life Sci.

    (2009)
  • E.L. Van der Kam et al.

    Differential effects of morphine on the affective and the sensory component of carrageenan-induced nociception in the rat

    Pain

    (2008)
  • C.J. Vierck et al.

    Clinical and pre-clinical pain assessment: are we measuring the same thing?

    Pain

    (2008)
  • H.C. Wang et al.

    Roles of corticosterone in formalin-induced conditioned place aversion in rats

    Neurosci. Lett.

    (2009)
  • G.T. Whiteside et al.

    An industry perspective on the role and utility of animal models of pain in drug discovery

    Neurosci. Lett.

    (2013)
  • R.X. Zhang et al.

    DAMGO in the central amygdala alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia

    Neuroscience

    (2013)
  • J.H. Broadbear et al.

    Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on kappa-opioid agonists in the mouse writhing assay

    Psychopharmacol. Berl.

    (1994)
  • L.E. Browne et al.

    Casting light on pain

    Nat. Biotechnol.

    (2014)
  • C.M. Cahill et al.

    Does the kappa opioid receptor system contribute to pain aversion?

    Front. Pharmacol.

    (2014)
  • Cited by (30)

    • Factors mediating pain-related risk for opioid use disorder

      2021, Neuropharmacology
      Citation Excerpt :

      Relatively transient pain models either do not alter or decrease morphine potency to produce CPP. For example, 10 mg/kg SC morphine was the minimum dose to produce CPP in adult male ICR mice using a single-conditioning session, and co-administration of IP acid as an acute noxious stimulus did not alter this morphine-induced CPP (Bagdas et al., 2016). Similarly, 10 mg/kg morphine IP produced a CPP in male Sprague-Dawley rats, and IPL carrageenan as a transient inflammatory stimulus did not affect this CPP, although it may have attenuated CPP produced by lower morphine doses (van der Kam et al., 2008).

    • Endogenous Opiates and Behavior: 2016

      2018, Peptides
      Citation Excerpt :

      Dexmedetmidine, alpha2-NE agonist induced naloxone-reversible CPP in rats [1036]. Highlights: Morphine, but not U50488H blocked visceral acid pain-induced conditioned place aversion in mice [65]. Glucocorticoids in the basolateral amygdala promoted the formation and expression of opiate withdrawal-associated aversive memories [306].

    View all citing articles on Scopus
    1

    Contributed equally to the manuscript.

    View full text