Indiana University-Purdue University Indianapolis (IUPUI) / Currently, changes to endogenous opioid circuits in various pain modalities, including surgical and neuropathic pain, remain unclear. Dynorphin, which is released by prodynorphin-expressing neurons (Pdyn+ neurons), is the endogenous opioid ligand to kappa opioid receptors (KOR). Moreover, a recent study has shown an increase in prodynorphin (Pdyn) mRNA expression in the prelimbic cortex (PL) in a mouse model of chronic pain. However, alterations in the activity of PL Pdyn-expressing neurons (PLPdyn+ neurons) in postoperative and chronic pain have never been explored. Firstly, I found that the population of PLPdyn+ neurons consists of both pyramidal and inhibitory subtypes. Secondly, I found that one day after surgical incision of the mouse hind paw, the excitability of pyramidal PLPdyn+ neurons was increased in both male and female mice, while the excitability of inhibitory PLPdyn+ neurons was unchanged. However, when postoperative pain behavior subsided, inhibitory PLPdyn+ neurons were hyperexcitable in male mice, while pyramidal PLPdyn+ neurons were hypoexcitable in female mice. Lastly, I dissected electrophysiological changes to PLPdyn+ neurons in the spared nerve injury (SNI) model of chronic neuropathic pain. At both early and late stages of SNI pain development, increased excitability of pyramidal PLPdyn+ neurons was detected in both male and female mice. However, in both male and female mice, the excitability of inhibitory PLPdyn+ neurons decreased 3 days after SNI but was conversely increased when measured 14 days after SNI. My findings suggest that different subtypes of PLPdyn+ neurons manifest distinct alterations in the development of different pain modalities in a sex-specific manner.

In clinical situations, most of the patients suffer from inflammation and acute postoperative pain after surgery. Postoperative pain has been emphasized as a very crucial issue in improving the quality of medical care in each medical center. Therefore, management of the postoperative pain is an effective approach to reduce the painful unpleasant feeling, complications, and death rate after surgery. Surgical trauma results in the induction of COX-2, leading to the release of prostaglandins, which sensitize peripheral nociceptors and increase the excitability of spinal neurons, producing pain hypersensitivity in the surrounding uninjured tissue.The purpose of this study is to test the preventive effect of COX-2 inhibitor SC-236 for post-operative pain by rat plantar incision model.Then, we explored whether SC-236 is more effective in reducing the hyperalgesia and inflammation response administered before incision than after incision. Furthermore, we used male Sprague-Dawley rats received plantar incision were used in this study, the rats received subcutaneous injection of SC-236 before or after plantar incision. Behavior teste of mechanical allodynia¡Bthermal hyperalgesia and COX-2 expression level was determined at 4 h and 1, 2, and 3 days after surgery. Mechanical allodynia was measured by mechanical withdrawal threshold that was determined by stimulating with von Frey filaments stimulation. Thermal hyperalgesia was measured by thermal withdrawal thermal tested by radioactive thermal assay. Mechanical allodynia¡Bthermal hyperalgesia and COX-2 expression level were measured at various time points by behavior teste¡Breal-time polymerase chain reaction¡Bwestern blot and immunohistochemistry. The data from pre-incisional injection of SC-236 was compared with that from post-incisional injection of SC-236.The results revealed pre-incisional injection of COX-2 inhibitor significantly inhibited thermal hyperalgesia but not mechanical allodynia then post-incisional injection of COX-2 inhibitor group. Skin of pre-incisional injection of SC-236 show significant decreased mRNA expression of COX-2 at 1 day and 2 day after incision evidenced by real-time polymerase chain reaction. Western blot and immunohistochemistry also show significant decreased protein expression of COX-2 at 4 hours and 1 day after incision. Therefore, pre-incisional administration of SC-236 could prevent the surgical wound induced thermal hyperalgesia and decrease mRNA and protein expression level of cutaneous COX-2 at 4 hours and one day after surgical incision compared to post-incisional administration of SC-236 .