Comparison of mechanical allodynia and the affective component of inflammatory pain in rats
Introduction
Pain experienced by humans and animals is the product of sensory and affective–motivational components (Auvray et al., 2008, Tracey and Mantyh, 2007). The emotional/affective aspect of pain is multifaceted and the immediate sensation of pain (sensory component) is distinct from the secondary pain affect (motivational component). Emotions related to pain, such as an increase in anxiety and depression, play a role in the response to painful stimuli. The affective–motivational component of pain involves the memory of past pain, the context of the pain, and the unpleasant emotional feelings of the long-term continuation of pain (Auvray et al., 2008, Tracey and Mantyh, 2007). Thus, emotions and mood significantly impact both chronic and acute pain sufferers (Tracey and Mantyh, 2007, Wiech et al., 2008). As evidenced, several recent clinical studies show that pain-related fear and anxiety are important in the experience and maintenance of pain behavior (Edwards et al., 2006, Gracely et al., 2004, Ploghaus et al., 2001, Porro et al., 2002).
Although there is a significant role of pain affect in the clinical experience of pain, there are few well-characterized preclinical pain models to assess the affective/emotional aspect of pain in animals. Most preclinical pain assays use a reflex based response to a mechanical or thermal stimulus. Using this approach, it is difficult to separate out the sensory versus affective effects of a pharmacological treatment (Pedersen and Blackburn-Munro, 2006). Although, there is some question about the clinical relevance of the results from experimental models of affective pain, similar brain areas have been shown to be important in the affective modulation of pain (Wiech and Tracey, 2009). Brain areas such as the periaqueductal grey (PAG), amygdala, and the anterior cingulate cortex (ACC) have been shown to play a role in affective pain processing in fMRI clinical studies as well as in preclinical models of affective component of pain (Fairhurst et al., 2007, LaGraize and Fuchs, 2007, LaGraize et al., 2004, Neugebauer et al., 2004, Rainville et al., 1997, Strigo et al., 2008). These similarities suggest that there is at least some overlap in mechanisms underlying the preclinical models of affective pain with clinical pain affect.
The effective doses of many analgesics in rodent models that use reflex measurements are much higher than those needed for pain relief in the clinic (Whiteside et al., 2008). Recent studies have suggested that morphine decreases the affective component of pain at doses that have no effect on the sensory component (LaGraize et al., 2006, van der Kam et al., 2007). A non-reflex behavioral measurement of pain that has been reported in the literature is the conditioned place escape avoidance paradigm (PEAP). This paradigm has previously been used to show that rats that have their injured paw stimulated show a very different response than those rats that are not in pain (LaBuda and Fuchs, 2000, LaBuda and Fuchs, 2001, Pedersen and Blackburn-Munro, 2006). In this procedure rats will avoid the black side of a black/white box when it is associated with stimulation of the injured paw and will spend more time on the white side when it is associated with stimulation of the non-injured paw. In contrast, rats that are not in pain will generally spend more time on the black side of the chamber.
The objectives of the current study were two-fold. First, further validate the place escape avoidance paradigm for the emotional/affective component of pain by using CFA to induce inflammatory pain and to test the response to pain relieving compounds in both vehicle and CFA-injected rats. Previous investigations with this model have not tested drug treatments in a non-pain control to assess compound effects on general behavior in PEAP. This consideration is important to ensure that drug treatment is not affecting anxiety levels which would also alter the time spent on the black side of the chamber in the non-pain controls. Because alterations in motor activity or working memory could confound the data, we assessed the compounds' effects on locomotor activity to appropriately interpret our results as these alterations would be the result of drug treatment. Secondly, the same compounds were tested in CFA-induced mechanical allodynia in order to compare the efficacy of the compounds on the sensory and affective aspects of pain. Compounds chosen for testing were celecoxib, diclofenac, duloxetine, fluoxetine, and scopolamine. Celecoxib and diclofenac were used based on their efficacy in inflammatory pain. Duloxetine was chosen based on its efficacy in chronic pain conditions, whereas fluoxetine was chosen due to the conflicting preclinical and clinical data regarding its efficacy in pain. Scopolamine has been shown to interfere with working memory tasks.
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Animals
Male Sprague–Dawley rats were obtained from Charles River (Portage, MI), weighing 180–320 g at the time of testing. For a given study, rats were weight matched between groups. Rats were housed in groups of 5–6 in a temperature and humidity controlled vivarium under a 12 h light-dark schedule with lights on at 0600. Food and water were available ad libitum except in the cases of oral dosing. In such cases, food was removed from the cages 24 h prior to testing and was returned immediately upon
Place escape/avoidance time course of behavior
A time course analysis was conducted on rats injected with CFA in their right hindpaw 48 h before testing versus naïve rats during the 30 min test. Percent time on the black side of the chamber was calculated from observations every 15 s during each 5 min period. There was a treatment (CFA vs. naïve) by time interaction [F(5,140) = 14.86, p < 0.01] and main effects of time [F(5,140) = 2.62, p < 0.05] and treatment [F(1,140) = 17.7, p < 0.01]. There were differences between CFA and naïve rats
Discussion
The current data show that celecoxib, diclofenac, duloxetine, but not fluoxetine and scopolamine, were able to decrease the aversion to stimulation of a CFA-injected paw in a non-reflex based model of affective pain. Additionally, celecoxib, diclofenac and duloxetine were able to do so at lower doses than needed to alter CFA-induced mechanical allodynia as assessed by paw withdrawal thresholds. Scopolamine had no effect on CFA-induced mechanical allodynia. Although fluoxetine dose-dependently
Acknowledgements
Thank you to Dr. Kaitlin Browman, Dr. Peer Jacobson, and Dr. Michael Jarvis for helpful comments on an earlier version of the manuscript and to Peter Curzon for help in setting up the model.
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