The role of the male rat infralimbic cortex in distraction analgesia.

Cognitive interventions, including distraction, have been successfully utilized in the manipulation of experimental pain and the treatment of clinical pain. Attentional diversions can reduce the experience of pain, a phenomenon known as distraction analgesia (DA). Prior research has suggested that variations in stimulus intensity may influence the magnitude of DA. However, the neural substrates of DA remain largely unknown. Converging evidence suggests that the infralimbic cortex (IL) in the brains of rats may contribute to the phenomenon of DA. The function of the rat IL in DA has never been directly investigated, therefore, this study sought to identify the role of the IL at two levels of noxious stimulus intensity among brain-intact and IL lesioned male rats within an established rat model of DA. A distractor object reduced formalin-induced nociceptive behavior in brain-intact rats, and this DA effect was detectable during low- (0.5% formalin) and high-intensity (1% formalin) stimulation. IL lesion resulted in a near-complete elimination of the DA effect and an overall reduction in formalin pain. These results provide the first known evidence that (i) the IL is involved in processing DA in rats, (ii) the IL contributes to formalin-induced nociceptive behavior irrespective of distraction, and (iii) a high-intensity stimulation was generally more susceptible to DA than low-intensity stimulation. These findings may further inform the mechanisms and future development of non-pharmacological strategies to reduce pain.

Assessing the aversive nature of pain with an operant approach/avoidance paradigm.

Preclinical pain assessments can be criticized for failing to adequately characterize the human clinical pain experience. Although recent assessments have improved upon this shortcoming, there are still significant limitations. One concern is that current procedures fail to examine underlying motivational drives related to pain. Therefore, we used a novel approach-avoidance paradigm that allowed a rat to either satisfy hunger or avoid noxious stimulation to reveal prioritizing of motivational drives. The operant paradigm utilized a single lever that the animal pressed for appetitive reward (approach). The lever press was associated with mechanical stimulation of an inflamed paw induced by subcutaneous injection of carrageenan (avoidance). The results revealed that carrageenan-injected animals had a significant suppression of lever pressing and, in addition, had a longer latency to approach and press a lever for appetitive reward. The pattern of operant behavioral responses indicates that the motivation to avoid pain superseded the motivation to alleviate hunger. Utilization of approach-avoidance paradigms, such as this one, can allow researchers to unravel the complexities of the pain experience with the goal of enhancing translation to clinical efficacy.

Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region.

The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21.

The elusive rat model of conditioned placebo analgesia.

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.

The place escape/avoidance paradigm: a novel method to assess nociceptive processing.

This paper summarizes a behavioral paradigm that was developed as a novel method to dissociate the multidimensional pain experience in rodents. The place escape/avoidance paradigm (PEAP) is based on the assumption that if animals escape and/or avoid a noxious stimulus, then the stimulus is aversive to the animal. Data is presented showing that when animals are placed in a specific environmental condition, they will perform purposeful behavior to escape and/or avoid the noxious stimulus. Additional data is presented to demonstrate the validity of the behavioral paradigm and how the paradigm has been used to test the hypothesis that the affective/motivational dimension of pain can be dissociated and studied independent of sensory pain processing. The behavioral paradigm highlights the emerging trend in the area of pain research and management towards developing more realistic behavioral paradigms to assess nociceptive processing in rodent models of chronic pain.