Abstract
Clinically relevant chronic pain is often associated with functional impairment and behavioral depression as an “affective/motivational” sign of pain; however preclinical animal models of inflammatory and neuropathic pain often produce weak evidence of impaired function. We hypothesized that hindpaw mechanical stimulation produced by a requirement to rear on a textured “NOX” plate would punish operant responding in rats treated with intraplantar complete Freund’s adjuvant (CFA, a model of inflammatory pain) or the chemotherapeutic paclitaxel (PTX, a model of neuropathic pain) and produce sustained pain-related depression of operant behavior. Male Sprague–Dawley rats were trained under a progressive-ratio (PR) schedule of food-maintained operant responding, then treated with CFA (100 µL in left hindpaw), PTX (2.0 mg/kg IP on alternate days for four total injections; 6.6 mg/kg IV on alternate days for three total injections), or saline vehicle. PR break points and mechanical thresholds for paw withdrawal from von Frey filaments were then tracked for 28 days. Subsequently, rats were tested with the opioid receptor antagonist naltrexone to assess latent sensitization and with the kappa opioid receptor (KOR) agonist U69593 to assess KOR function. CFA produced significant mechanical hypersensitivity for 3 weeks but decreased PR breakpoints for only 1 day. Both IP and IV PTX produced mechanical hypersensitivity for at least three weeks; however, only IV PTX decreased PR breakpoints, and this decrease was not alleviated by morphine. After recovery, naltrexone reinstated mechanical hypersensitivity in CFA- but not PTX-treated rats, and it did not reinstate depression of breakpoints in any group. U69593 dose-dependently decreased PR breakpoints in all groups with no difference between control vs. CFA/PTX groups. These results suggest that rearing on a textured NOX plate was not sufficient to punish operant responding in CFA- and PTX-treated rats despite the presence of sustained mechanical hypersensitivity. The rapid recovery of operant responding could not be attributed to latent sensitization, KOR downregulation, or behavioral tolerance. These results extend the range of conditions under which putative chronic pain manipulations produce weak evidence for depression of operant responding as a sign of the “affective/motivational” component of pain in rats.
Highlights
Relevant chronic pain states in human and veterinary medicine are often associated with functional impairment, and restoration of function is a common goal of pain treatment (Dworkin et al, 2005; Jensen et al, 2007; Brown et al, 2008)
Rats in the IV paclitaxel group were surgically implanted with IV catheters and allowed to recover for one week prior to initiation of paclitaxel treatment, and mean ± SEM break points in this group did not differ at the conclusion of operant training (22.9 ± 1.5), on the day after surgery (22.0 ± 2.9), or after the one-week recovery period (24.9 ± 2.6)
This study examined the degree to which mechanical stimulation to the hindpaws might elicit the “affective/motivational” component of chronic pain as indicated by pain-related punishment of operant responding maintained under a PR schedule of food delivery in rats treated with either Ipl Complete Freund’s adjuvant (CFA) or repeated paclitaxel
Summary
Relevant chronic pain states in human and veterinary medicine are often associated with functional impairment, and restoration of function is a common goal of pain treatment (Dworkin et al, 2005; Jensen et al, 2007; Brown et al, 2008). Fuchs and colleagues developed a “place escape-avoidance procedure” (PEAP) in which inflammatory and neuropathic pain models were supplemented by acute, response-contingent mechanical stimulation to the affected paw (LaBuda and Fuchs, 2000a; LaBuda and Fuchs, 2000b) In this procedure, rats received intraplantar injection of complete Freund’s adjuvant (Ipl CFA, an inflammatory pain model) or unilateral L5 nerve ligation (a surgical mononeuropathy model) one or two days, respectively, before a sequence of two test days. This behaviorally contingent mechanical stimulation significantly reduced time in the dark compartment, indicating that mechanical stimulation of the injured paw functioned as a punisher of locomotion in the dark compartment, and a parallel study found that morphine blocked this punishment This type of acute stimulus delivery is labor intensive, but Boada and colleagues recently developed a strategy to simplify mechanical stimulus delivery to the feet of rats with a nerve injury model of neuropathic pain (Boada et al, 2016). Mechanical stimulation (delivered via the rat’s body weight pressing its paw onto the pyramids) was contingent on locomotion in the different quadrants, and nerve-injured rats avoided the quadrant with the sharpest (0.2 mm2) pyramids, indicating that mechanical stimulation associated with these sharper pyramids punished locomotion in those quadrants
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