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. 2018 Dec;34(6):1047-1057.
doi: 10.1007/s12264-018-0279-6. Epub 2018 Sep 3.

A Context-Based Analgesia Model in Rats: Involvement of Prefrontal Cortex

Lingchi Xu  1 , Yalan Wan  2 , Longyu Ma  1 , Jie Zheng  1 , Bingxuan Han  1 , Feng-Yu Liu  1 , Ming Yi  1 , You Wan  3   4   5   6
Affiliations

A Context-Based Analgesia Model in Rats: Involvement of Prefrontal Cortex

Lingchi Xu et al. Neurosci Bull. 2018 Dec.

Abstract

Cognition and pain share common neural substrates and interact reciprocally: chronic pain compromises cognitive performance, whereas cognitive processes modulate pain perception. In the present study, we established a non-drug-dependent rat model of context-based analgesia, where two different contexts (dark and bright) were matched with a high (52°C) or low (48°C) temperature in the hot-plate test during training. Before and after training, we set the temperature to the high level in both contexts. Rats showed longer paw licking latencies in trials with the context originally matched to a low temperature than those to a high temperature, indicating successful establishment of a context-based analgesic effect in rats. This effect was blocked by intraperitoneal injection of naloxone (an opioid receptor antagonist) before the probe. The context-based analgesic effect also disappeared after optogenetic activation or inhibition of the bilateral infralimbic or prelimbic sub-region of the prefrontal cortex. In brief, we established a context-based, non-drug dependent, placebo-like analgesia model in the rat. This model provides a new and useful tool for investigating the cognitive modulation of pain.

Keywords: Cognition modulation; Context-based analgesia; Hot-plate test; Opioid system; Pain; Placebo analgesia; Prefrontal cortex.

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Conflict of interest statement

The authors claim no competing interests.

Figures

Fig. 1
Fig. 1
Training and probe flowchart for the context-based analgesic effect in rats. Three groups were trained and tested in the three-phase experimental paradigm (Baseline: left column; Training: middle column; Probe: right column). Contexts A (black) and B (grey) were in the same room but brightly- and dimly-lit, respectively. HT, high temperature (52°C); LT, low temperature (48°C).
Fig. 2
Fig. 2
Establishment of the context-based analgesia model in rats. Three groups were trained and tested in the three-phase experimental paradigm. Context A (black) was a bright room whereas Context B (grey) was a dim room. Paw licking latencies (PLLs) of Test group 1 (A), Test group 2 (B), and Control group (C) in the baseline, training and probe phases are shown. The different contexts modulated pain perception with the same hot-plate temperature in the probe test. The context-based analgesic effect was indicated by the differential PLLs between baseline and the probe test with the same context and hot-plate temperature. n = 8, *P < 0.05, **P < 0.01, paired t test.
Fig. 3
Fig. 3
Naloxone blockade of the context-based analgesic effect in rats. A Training and testing paradigm. B Naloxone injection affected PLLs in the hot-plate test. In contrast, the context-based analgesia was not influenced by saline injection. Context A, black; Context B, grey; HT, high temperature; LT, low temperature. n = 10, *P < 0.05, **P < 0.01, paired t test.
Fig. 4
Fig. 4
Confirmation of optogenetic inhibition or inhibition of neuronal firing in pyramidal neurons. A Schematic of the implanted optic fibers: in the left hemisphere tilted 20°, and vertical on the right side. B EYFP expression in excitatory PL/IL neurons after viral injection. C Examples of yellow light-induced outward current and membrane hyperpolarization in a neuron expressing ArchT. An IPSC (left), IPSP (middle), and inhibition of APs were induced by the yellow light stimulation. D Example of a blue light-evoked EPSC recorded in an EYFP-tagged ChR2-expressing neuron (left). Current clamp recordings under either continuous blue-light stimulation or in response to blue light delivered at interpulse intervals of 0.5 s. The pulse-locked neuronal firing was induced by the blue light, confirming the expression and function of ChR2 in the pyramidal neuron (middle and left).
Fig. 5
Fig. 5
Optogenetic activation of either PL or IL excitatory neurons blocked the context-based analgesic effect in rats. A Training and probe paradigm. B Optogenetic activation of neurons in either PL or IL cortex affected PLLs in the hot-plate test. Note that the context-based analgesia was significantly decreased with LED-on but not with LED-off. Context A, black; Context B, grey; HT, high temperature; LT, low temperature. n = 10 in both PL and IL groups, *P < 0.05, **P < 0.01, paired t test.
Fig. 6
Fig. 6
Optogenetic inhibition of either PL or IL excitatory neurons blocked the context-based analgesic effect in rats. A Training and probe paradigm. B Optogenetic inhibition of neurons in either the PL or IL cortex abolished the PLL difference between the two contexts in rats showing context-based analgesia. Note that PLLs were not influenced at light-off during the hot-plate test. Context A, black; Context B, grey; HT, high temperature; LT, low temperature. n = 10 in the PL group and n = 11 in the IL group, *P  < 0.05, paired t test.
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