Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of c-aminobutyric acid A receptors(GABA_ARs), which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-performance liquid chromatography/tandem mass spectrometry,we found increased levels of neurosteroids(pregnenolone,progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone) in the chronic stage of neuropathic pain(28 days after spared nerve injury) in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus(AP-3.0 mm, ML ±3.0 mm, DV 6.0 mm)alleviated the mechanical allodynia in neuropathic pain,while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were significantly attenuated by the GABA_AR antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.
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.
Lingchi XuYalan WanLongyu MaJie ZhengBingxuan HanFeng-Yu LiuMing YiYou Wan
