Resistance of Food-Maintained Operant Responding to Mechanical Punishment in Rats: Further Evidence for Weak “Affective/Motivational Pain” in Rat Models of Inflammatory and Neuropathic Pain

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.

Bone marrow‐derived mesenchymal stem cells attenuate complete Freund's adjuvant‐induced inflammatory pain by inhibiting the expression of P2X3

“…A persistent inflammatory pain model was established according to a previously reported procedure 30 . Briefly, 0.1 mL CFA (Sigma–Aldrich, St. Louis, MO) was injected into the plantar surface of the left hind paw of rats under anaesthesia with 1.5–2.5% isoflurane treatment.…”

“…Six-week-old male Sprague-Dawley rats (200 ± 20 g) were purchased from SPF (Beijing) Biotechnology Co., Ltd (production licence number: A persistent inflammatory pain model was established according to a previously reported procedure. 30 Briefly, 0.1 mL CFA (Sigma-Aldrich, St. Louis, MO) was injected into the plantar surface of the left hind paw of rats under anaesthesia with 1.5-2.5% isoflurane treatment. For the sham group, an equal volume of saline was injected in the same place of the left hind paw on the rats as the injection of CFA with or without treatment.…”

The Use of an FR1 Schedule Operant Approach-Avoidance Paradigm to Measure the Aversiveness of Neuropathic and Inflammatory Pain

“…Theoretically, operant paradigms have the ability to measure changes in behavior and prioritization of drives as a result of disruption by pain. However, there are also possibilities that preclinical chronic pain manipulations have produced weak evidence for the depression of operant responding as a sign of the motivational components of pain or pain affect ( 53 ). Taken together, it still remains unclear what exactly the AAP is quantifying since there was no lever-press suppression in the unilateral pain conditions, an outcome that was previously seen in a single lever paradigm by ( 30 ) used similar aspects of the AAP.…”