臺灣博碩士論文加值系統

辣椒素受體主要表現在感覺神經細胞上，其在痛覺的傳遞及發炎反應所產生的熱痛過敏現象中扮演重要的角色。我們實驗室先前的研究發現，硫酸孕烯醇酮 (PS) 可抑制雄性大白鼠背根神經節細胞膜上的辣椒素受體所媒介的電流反應及急性痛覺反應，而雌性類固醇雌二醇 (E2) 則對辣椒素受體所媒介的此二種反應，具有增強的作用。但是PS和E2對辣椒素誘發大白鼠產生的熱痛過敏現象是否也具有調節作用，目前則依然不甚清楚。因此在本研究中，我們利用藥理學的方法和動物痛覺行為的測試技術，探討PS及E2對辣椒素誘發雄性大白鼠產生熱痛過敏現象及急性痛覺反應的調節作用及其機制。我們的結果顯示，於腳掌注射PS 可抑制辣椒素所誘發的熱痛過敏現象，且其抑制作用呈現劑量依賴效應。單獨給予PS不會改變大白鼠對熱痛的敏感度，顯示PS的抑制作用並非透過增加大白鼠對熱痛的閾值所導致。此外，PS的抑制作用不會受到去磷酸酶的抑制劑FK506所阻斷，表示PS並非透過活化去磷酸酶來達到其抑制作用。於腳掌內注射E2可以增加辣椒素所誘發的熱痛過敏現象。此外，同時給予E2及低於閾值劑量的辣椒素則會產生熱痛過敏現象，表示E2可降低誘發熱痛過敏象所需辣椒素劑量的閾值。但如同時給予17α-E2及低於閾值劑量的辣椒素則不會產生熱痛過敏現像，顯示E2的作用具有立體結構的專一性。單獨注射E2並不會改變大白鼠對熱痛的敏感度。給予辣椒素受體的抑制劑，可以阻斷同時給予E2和低於閾值劑量之辣椒素所誘發的熱痛過敏現象，表示其誘發的熱痛過敏現象是經由辣椒素受體媒介的。此外，給予磷酸激酶C或磷酸激酶A的抑制劑可阻斷由同時給予E2和低於閾值劑量的辣椒素所誘發的熱痛過敏現象，顯示磷酸激酶C和磷酸激酶A有參與E2和辣椒素對熱痛過敏現象的協同作用上。相反地，磷酸激酶C或磷酸激酶A的抑制劑則無法阻斷E2對辣椒素所誘發急性痛覺反應的促進作用。綜合上述結果可知，PS並非經由活化去磷酸酶來抑制辣椒素所誘發的熱痛過敏現象，而磷酸激酶C和磷酸激酶A則有參與E2降低誘發熱痛過敏現象所需的辣椒素閾值，但並不參與E2對辣椒素所誘發急性痛覺反應的增強作用。

The capsaicin receptor is expressed predominantly by sensory neurons and has been implicated in nociception and inflammatory thermal hyperalgesia. Previous studies from our laboratory have shown that the neurosteroid pregnenolone sulfate (PS) inhibits, but the female sex steroid 17β-estradiol (E2) potentiates, both the capsaicin receptor-mediated current in male rat dorsal root ganglion neurons and the capsaicin receptor-mediated nocifensive response in male rats. However, it is unclear whether PS and E2 also have modulatory effects on capsaicin-induced thermal hyperalegsia. In the present study, we used pharmacological methods and nociceptive behavioral tests to characterize the effects of PS and E2 on capsaicin-induced heat hypersensitivity and nocifensive responses in male rats in vivo. Our results revealed that intraplantar injection of PS dose-dependently attenuated capsaicin-induced thermal hyperalgesia. PS alone had no effect on heat sensitivity, indicating that the effect of PS on capsaicin-induced thermal hyperalgesia was not due to an increase in nociceptive threshold. Moreover, inhibition by PS of capsaicin-induced thermal hyperalgesia was not reduced by FK506, a selective calcineurin inhibitor, suggesting that the effect of PS was not mediated by calcineurin. Furthermore, intraplantar injection of E2 potentiated capsaicin-induced thermal hyperalgesia in male rats. In addition, co-injection of E2 but not 17α-estradiol with a subthreshold dose of capsaicin induced thermal hyperalgesia, indicating that the reduction by E2 of the capsaicin threshold for thermal hyperalgesia was stereospecific. E2 alone did not alter the heat sensitivity. Administration of capsazepine, a capsaicin receptor antagonist, blocked thermal hyperalgesia induced by co-injection of subthreshold doses of E2 and capsaicin, suggesting that thermal hyperalgesia was mediated by the capsaicin receptor. Furthermore, pretreatment of a protein kinase C (PKC) or a PKA inhibitor completely inhibited the synergistic effect of co-injected capsaicin and E2 on thermal hyperalgesia, arguing strongly for the involvement of PKC and PKA. In contrast, administration of PKC or PKA inhibitor did not block the potentiating effect of E2 on capsaicin-induced nocifensive responses. In conclusion, these data demonstrate that PS inhibits capsaicin-induced heat hypersensitivity via a calcineurin-independent mechanism, and that PKC and PKA are involved in the reduction by E2 of the capsaicin threshold for thermal hyperalgesia but not in the potentiating effect of E2 on capsaicin-induced nocifensive responses.

Table of Contents…………………………………………………………Ⅱ
List of Figures………………………………………………………Ⅳ
Abstract in Chinese…………………………………………………1
Abstract…………………………………………………………………3
Introduction……………………………………………………………5
Capsaicin, TRPV1, nociception, and thermal hyperalgesia…5
Modulation by neurosteroids of amino acid transmitter receptor-mediated responses……………………………6
Modulation by neurosteroids of TRPV1-mediated currents, nocifensive responses, and thermal hyperalgesia……………7
Rationale and specific aims of this study……………………9
Materials and Methods………………………………………………10
Animals………………………………………………………………10
Plantar test………………………………………………………10
Capsaicin test.……………………………………………………11
Drugs and Chemicals………………………………………………11
Statistical analysis……………………………………………12
Experiment design……………………………………………………12
Results………………………………………………………15
PS dose-dependently inhibits capsaicin-induced thermal hyperalgesia…………15
PS does not act through calcineurin to inhibit capsaicin-induced thermal hyperalgesia……………………16
FK506 potentiates the capsaicin-induced nocifensive response……………16
E2 potentiates capsaicin-induced thermal hyperalgesia ………………………17
E2 stereospecifically reduces the capsaicin threshold for thermal hyperalgesia………………………………………………17
TRPV1 mediates thermal hyperalgesia induced by co-injection of subthreshold doses of capsaicin and E2………18
PKC and PKA are involved in the synergistic effects of co-injected capsaicin and E2 on thermal hyperalgesia…………19
E2 potentiates the capsaicin-induced nocifensive response through a PKC- and PKA-independent mechanism………………19
Discussion……………………………………………………………21
PS attenuates capsaicin-induced thermal hyperalgesia……21
E2 potantiates capsaicin-induced thermal hyperalgesia and reduces the capsaicin threshold for thermal hyperalgesia…………23
TRPV1 mediates thermal hyperalgesia induced by co-injection of subthreshold doses of capsaicin and E2………25
Mechanisms underlying potentiation by E2 of capsaicin-induced thermal hyperalgesia and nocifensive responses…25
A proposed model for E2 enhancing effect on capsaicin-induced nociception and thermal hyperalgesia………………29
Conclusion…………………………………………………………29
References………………………………………………………46
About the Author…………………………………………………61



List of Figures
Figure 1. Time course of normalized PWLs to a noxious radiant heat stimulus before and after i.pl. injection of vehicle, capsaicin, capsaicin plus PS, or PS in male rats……………………………………………………………………31

Figure 2. PS inhibits capsaicin-induced thermal hyperalgesia in a dose-dependent manner at 15 min after drug injection…………………………………………………32

Figure 3. PS does not act through calcineurin to inhibit capsaicin-induced thermal hyperalgesia………………………33

Figure 4. Pretreatment of FK506 does not block the inhibitory effect of PS on capsaicin-induced thermal hyperalgesia at 15 min after injection of capsaicin plus PS……………………………………………………………………34

Figure 5. Pretreatment of FK506 enhances the capsaicin-induced nocifensive response in male rats……………………………………………………………………35

Figure 6. E2 potentiates capsaicin-induced thermal hyperalgesia…………………36

Figure 7. Comparison of PWL differences among groups of rats injected with capsaicin, capsaicin plus E2, and E2 at 15, 30, 60, and 120 min after drug injection……………37

Figure 8. E2 stereospecifically reduces the capsaicin threshold for thermal hyperalgesia……………………………38

Figure 9. Comparison of PWL differences among groups of rats injected with capsaicin, capsaicin plus E2, and capsaicin plus 17��-E2 at 15, 30, 60, and 120 min after drug injection………………………………………………………39

Figure 10. TRPV1 mediates thermal hyperalgesia induced by co-injection of subthreshold doses of capsaicin and E2…………………………………………………40

Figure 11. Comparison of PWL differences among groups of rats preinjected with vehicle or capsazepine, followed by injection of E2, capsaicin, or capsaicin plus E2 at 15, 30, 60, and 120 min after the second injection……………41

Figure 12. PKC and PKA are involved in the synergistic effects of co-injected capsaicin and E2 on thermal hyperalgesia…………………………………………42

Figure 13. Comparison of the PWL differences among groups of rats preinjected with vehicle, Bis I, or H89, followed by injection of capsaicin plus E2 at 15, 30, 60, and 120 min after drug injection…………………………………………43

Figure 14. E2 potentiates the capsaicin-induced nocifensive response through a PKC- and PKA-independent mechanism ……………………………………………………44

Figure 15. A proposed model for E2 enhancing effect on capsaicin-induced nociception and thermal hyperalgesia……………………………………………………45

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