The elusive rat model of conditioned placebo analgesia

Abstract

Recent research on human placebo analgesia has suggested the need for rodent models to further elucidate the neural substrates of the placebo effect. This series of 3 experiments therefore was performed in an attempt to develop a model of placebo analgesia in rats. In each study, female Sprague-Dawley rats received an L5 spinal nerve ligation to induce a neuropathic pain condition. Each rat then underwent a 4-day conditioning procedure in which an active analgesic drug or its vehicle (unconditioned stimulus) was associated with the following cues (conditioned stimuli): novel testing room (environmental), vanilla scent cue (olfactory), dim incandescent lighting (visual), restraint procedure/injection (tactile), and time of day and injection-test latency (temporal). The analgesics for each experiment were as follows: Experiment 1 used 90 mg/kg gabapentin, experiment 2 used 3mg/kg loperamide hydrochloride, and experiment 3 used 6 mg/kg morphine sulfate. On the following test day, half of the animals received the opposite treatment, resulting in 4 conditioning manipulations: drug/drug, drug/vehicle, vehicle/drug, and vehicle/vehicle. Nociceptive thresholds were assessed with the mechanical paw withdrawal threshold test each day after the conditioning procedure. In all 3 experiments, no significant differences were detected on test day between control and placebo groups, indicating a lack of a conditioned placebo analgesic response. Our results contrast with prior research that implies the existence of a reliable and robust response to placebo treatment. We conclude that placebo analgesia in rats is not particularly robust and that it is difficult to achieve using conventional procedures and proper experimental design.

Relieving pain using dose-extending placebos: a scoping review

“…Although negative results have been reported [58], this research suggested that animals learn to associate contextual cues with elevated pain tolerance producing conditioned analgesia.…”

<p>Remote Analgesic Effects Of Conventional Transcutaneous Electrical Nerve Stimulation: A Scientific And Clinical Review With A Focus On Chronic Pain</p>

“…66,167 However, placebo responses are unlikely to account completely for the remote analgesic effects of conventional TENS. First, the existence of robust animal and human experimental pain data, which are less sensitive to placebo than clinical pain, 168,169 argues against a primary role for a placebo mechanism. Second, the placebo response is driven by expectation, 170 and it seems unlikely that patients will have a strong expectation of pain relief from a device located at a distance from their pain.…”

Placebo Analgesia in Rodents: Current and Future Research

“…To our knowledge, the first published study on an attempt to develop a model of placebo analgesia in chronic pain was by McNabb, White, Harris, and Fuchs (2014). They used a well-established and characterized model of persistent peripheral neuropathic pain—unilateral spinal nerve ligation in female rats (Kim & Chung, 1992).…”

“…The authors carefully concluded that placebo analgesia of chronic pain is “not particularly robust.” They also postulated that the failure to evoke placebo analgesia may reflect: (1) the severity of the spinal nerve injury model, suggesting that intense, chronic pain may not be subject to placebo analgesia; (2) the relatively slow time course of the analgesics used, resulting in inadequate temporal alignment of the conditioning cues; and (3) the reliance on only a reflexive measure of tactile sensitivity, suggesting that addressing these issues might reveal placebo analgesia in animal models of chronic pain (McNabb et al, 2014). …”

“…Whereas McNabb et al (2014) used 4 days of conditioning, it would be important to increase the number of conditioning days, because the strength of the conditioned placebo response may increase with the number of cue associations (Ader & Cohen, 1982; Niemi et al, 2007). …”