Nalbuphine attenuates morphine-induced scratching by inhibiting PKCß-dependent microglial activation and p38 phosphorylation in male mice.

Morphine-induced scratching (MIS) is a common adverse effect associated with the use of morphine as analgesia after surgery. However, the treatment of MIS is less than satisfactory due to its unclear mechanism, which needs to be enunciated. We found that intrathecal (i.t.) injections of morphine significantly enhanced scratching behavior in C57BL/6J male mice as well as increased the expressions of protein kinase C ß (PKCß), phosphorylated p38 mitogen-activated protein kinases (MAPK), and ionized calcium-binding adapter molecule 1 (Iba1) within spinal cord dorsal horn. Conversely, using the kappa opioid receptor antagonist nalbuphine significantly attenuated scratching behavior, reduced PKCß expression and p38 phosphorylation, and decreased spinal dorsal horn microglial activation, while PKCδ and KOR expression elevated. Spinal PKCß silencing mitigated MIS and microglial activation. Still, knockdown of PKCδ reversed the inhibitory effect of nalbuphine on MIS and microglial activation, indicating that PKCδ is indispensable for the antipruritic effects of nalbuphine. In contrast, PKCß is crucial for inducing microglial activation in MIS in male mice. Our findings show a distinct itch cascade of morphine, PKCß/p38MAPK, and microglial activation, but an anti-MIS pathway of nalbuphine, PKCδ/KOR, and neuron activation.

Bone mesenchymal stem cells attenuate resiniferatoxin-induced neuralgia via inhibiting TRPA1-PKCδ-P38/MAPK-p-P65 pathway in mice.

Treatment of neuropathic pain (NP) resulting from nerve injury is one of the most complicated and challenging in modern practice. Pharmacological treatments for NP are not fully effectively and novel approaches are requisite. Recently, transplantation of bone mesenchymal stem cells (BMSCs) has represented a promising approach for pain relief and neural repair, but how it produces beneficial effects on resiniferatoxin (RTX) induced nerve injury is still unclear. Here, we identified the BMSCs' analgesic effects and their potential mechanisms of microglial cells activation on RTX induced neuralgia. Immunostaining, biochemical studies demonstrated that microglia rather than astrocyte cells activation involved in RTX induced mechanical hyperalgesia, whereas the GFP-labeled BMSCs alleviated this mechanical hyperalgesia. Moreover, pain-related TRPA1, PKCδ, CaMKIIɑ (Calcium/calmodulin dependent protein kinase II), P38/MAPK (mitogen-activated protein kinase), p-P65 activation and expression in the spinal cord were significantly inhibited after BMSC administration. In addition, BMSCs treated RTX mice displayed a lower density of mushroom dendritic spines. Our research suggested that activation of PKCδ-CaMKIIɑ-P38/MAPK-p-P65 pathway and mushroom dendritic spines abnormal increase in the spinal cord is the main mechanism of RTX induced neuropathic pain, and transplant of BMSCs to the damaged nerve may offer promising approach for neuropathic pain.

Modulation of NR1 receptor by CaMKIIα plays an important role in chronic itch development in mice.

Intractable scratching is the characteristic of chronic itch, which represents a great challenge in clinical practice. However, the mechanism underlying chronic itch development is largely unknown. In the present study, we investigated the role of NMDA receptor in acute itch and in development of chronic itch. A mouse model was developed by painting DNFB to induce allergic contact dermatitis (ACD). We found that the expression of pNR1, which is a subunit of NMDA receptor, was significantly increased in the dorsal root ganglion in the DNFB model. The DNFB-evoked spontaneous scratching was blocked by the NMDA antagonist D-AP-5, the calcium-calmodulin-dependent protein kinase (CaMK) inhibitor KN-93, a CaMKIIα siRNA and the PKC inhibitor LY317615. Moreover, activation of PKC did not reverse the CaMKIIα knockdown-induced decrease in scratching, suggesting that PKC functions upstream of CaMKIIα. Thus, our study indicates that modulation of NR1 receptor by CaMKIIα plays an important role in the development of chronic itch.