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Neuroplasticity In The Processing Of Nociceptive Information: Role Of Glial Cells, Interleukin-2 And Somatostatin SSTR2A Receptors

Posted on:2003-12-07Degree:DoctorType:Dissertation
Country:ChinaCandidate:P SongFull Text:PDF
GTID:1104360092970755Subject:Neurobiology
Abstract/Summary:PDF Full Text Request
Neuroplasticity in the processing of nociceptive information: role of glial cells, interleukin-2 and somatostatin SSTR2A receptors Ping Song (Neurobiology)Directed by Zhi-Qi Zhao, Ph.D., ProfessorThe present study was designed to investigate the role of glial cells, interleukin-2 (IL-2) and somatostatin (SST) 2A receptor (SSTR2A) in the development of morphine tolerance, hyperalgesia induced by chronic constriction injury (CCI) and complete Freund's adjuvant (CFA) using behavioral, electrophysiological, immunohistochemistry, biochemistry and molecular biology methods. The main results are as follows:1. Repeated systemic administration of morphine led to significant increase in glial fibrillary acidic protein (GFAP), a specific marker for astroglial cells,in the spinal cord, posterior cingulate cortex and hippocampus but not in the thalamus. This increase was attributed primarily to hypertrophy of astroglial cells rather than their proliferation or migration. When chronic morphine (20μg/2μl, i.t.) was delivered in combination with fluorocitrate (1nmol/1μl, i.t.), a specific and reversible inhibitor of glial cells, spinal tolerance to morphine analgesia was partly but significantly attenuated as measured by behavioral test and the increase in spinal GFAP immunostaining was also greatly blocked. The present investigation provides the first evidence for the role of glial cells in the development of morphine tolerance in vivo. 2. IL-2, a cytokine known as T-cell growth factor, exerts antinociceptive effect. Intraplantar injection of IL-2 significantly enhanced pain threshold as measured by paw withdrawal latency (PWL) to noxious radiant heat in normal rats. RT-PCR analysis further showed that IL-2R ( and ( chain were constitutively expressed in normal rat dorsal root ganglion (DRG) neurons. Immunohistochemistry further demonstrated that IL-2R α chain was mainly localized to small and medium-sizedneurons, which are predominantly responsible for nociceptive transmission. With whole-cell patch clamp recordings on capsaicin-sensitive small DRG neurons, we observed that IL-2 significantly inhibited transient high-threshold Ca2+ currents and depolarization-evoked increase in intracellular calcium concentration. All the effects of IL-2 were blocked by naloxone. Intraplantar injection of IL-2 significantly enhanced pain threshold to noxious radiant heat in normal rats. After administration of IL-2, PWLs were also markedly increased in morphine-tolerant and CCI-operated rats, which have been proven morphine-insensitive. IL-2-induced antinociception in both morphine-tolerant and CCI-operated rats was significantly lower than that in normal rats. IL-2-induced antinociception was partially blocked by naloxone in normal rats but remained unchanged in CCI group. Here we infer that μ opioid receptors play a critical role in IL-2-induced antinociception and that there are also some other receptors involved in this process. Clinical use of IL-2 may be extended to cure for neuropathic pain 3. In normal rats, intrathecal pre-treatment with polyclonal antiserum against SSTR2A receptor did not affect PWL or pinch threshold. Significant attenuation of the thermal, but not mechanical, hyperalgesia induced by CFA was observed after pre-treatment with the antiserum. Both immunohistochemistry and immunoblotting analysis showed a significant increase in SSTR2A receptor content in the spinal cord 6 h after noxious thermal stimulation that lasted for at least 24 hours in normal rats. However, there were no notable changes in SSTR2A receptor content within 24 h after noxious mechanical stimulation. The present findings provide the first evidence that SSTR2A receptors are responsible for thermal, but not mechanical, nociceptive transmission in the spinal cord. The results also support the notion that different transmitters and/or receptors are involved in different types of nociceptive processing.
Keywords/Search Tags:Spinal cord, Dorsal root ganglion, Antinociception, Hyperalgesia
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