Activation of mitogen-activated protein kinase (MAPK) enzymes in nociceptive plasticity has been extensively studied. P38 MAPK enzyme, which can be activated by cytokines, acts as a crucial intracellular regulator of environmental changes. The aim of this study was to elucidate the cellular events during arthritis-induced hyperalgesia that are mediated by interleukin-6 and p38 MAPK, and their effects on the expression of spinal mu-opioid receptors (MORs), in different stages of arthritis in male Wistar rats. Complete Freund's adjuvant (CFA)-induced arthritis (AA) was caused by subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 antibody and p38 MAPK phosphorylation inhibitor were administered during 21 days of study. Spinal MOR, p38, and phosphorylated-p38 (pp38) proteins expressions were detected by Western blotting. Daily treatment with anti-IL-6 antibody and p38 MAPK phosphorylation inhibitor, SB203580, significantly decreased paw edema in AA group. Daily anti-IL-6 and SB203580 administration caused a significant reduction in hyperalgesia in the first week of the study, but increased hyperalgesia in the next 2 weeks in experimental groups compared to the AA control group. Expression of pp38 MAPK protein significantly decreased on the 3, 7, 14, and 21 days in AA+SB203580 and AA+anti-IL6 groups compared to AA group. Additionally, daily treatment with anti-IL6 antibody and SB203580 in AA group caused significantly decrease in spinal MOR expression compared to AA control group. The results of our study can confirm that activated spinal p38 MAPK enzyme may play an important role in cellular IL-6 signaling pathways in hyperalgesia variation during different stages of AA inflammation. Also, it can be suggested that at least a part of p38 MAPK effects on hyperalgesia is mediated by spinal MOR expression variation.

The anti-inflammatory and anti-nociceptive properties of Rosmarinus officinalis L. (ROL) extract and its major constituent, carnosol in male NMRI mice (W:25-30 g) have been evaluated in the present study. Formalin (2%, 20 microL) was injected into the plantar portion of the hind paw and resulting pain and inflammation was studied for 60 min. The plant extract, carnosol and other drugs were administered intraperitoneally or subcutaneously 30 min before formalin injection. In a separate experiment, the effects of the extract and carnosol on plasma corticosterone levels and activity of the enzymes cyclooxygenase type 1 and 2 (COX1 and COX2) were investigated. Injection of different doses of ROL and carnosol reduced pain in the phase 2 of the formalin test, which was not inhibited by naloxone and/or memantine. In addition, pretreatment of the animals with ROL and/or carnosol reduces the formalin-induced inflammation. Furthermore, the extract and carnosol did not affect plasma corticosterone levels compared with the control group. Interestingly, both the extract and carnosol inhibited COX1 and COX2 activity. It could be concluded that ROL extract and carnosol suppressed pain and inflammation induced by formalin injection, which may be due to inhibition of COX1 and COX2 enzymes activity.

Our study confirmed that a part of anti- inflammatory effects of serum IL10 during AA inflammation was mediated via inhibition of p38MAPK enzyme phosphorylation. Moreover, these findings suggest that increase in the level of spinal mu opioid receptor expression during AA inflammation is not mediated via the direct effect of serum IL10 on spinal p38MAPK.

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Opioid receptors play an important role in modulation of hyperalgesia in inflamed tissues, but chronic morphine application induces such side effects as tolerance. There is near communications between cytokines and mu opioid receptor expression. This study was aimed to assess the role of serum IL-10 in morphine tolerance development during adjuvant-induced arthritis. Adjuvant arthritis (AA) was induced on day 0 by single injection of Complete Freund's Adjuvant (CFA) into the rats' hindpaw. Hyperalgesia, edema, and spinal mu opioid receptor (mOR) variations were assessed on 0, 7, 14, and 21 days of the study. For assessment of the morphine tolerance development, morphine effective dose (4 mg/kg) was administered from the 14th day after CFA injection and continued until the morphine post-dose paw withdrawal latency (PWL); it did not significantly differ from the baseline. For assessment of the effects of IL-10 on tolerance induction, a neutralizing dose (ND50) of anti-IL-10 was administered daily during different stages of the study. AA induction in the right hindpaw of rats resulted in unilateral inflammation and hyperalgesia within 21 days of the study. Anti-IL-10 antibody administration in the AA rats induced marked elevation of hyperalgesia compared to the AA control group. Our data also indicated that morphine effective anti-hyperalgesic dose significantly decreased in the AA rats compared to the control group, which this symptom was aligned with spinal mu opioid receptor (mOR) expression increase during AA. Moreover, there was a significant difference in morphine tolerance induction between the AA and control rats, and our results also demonstrated that IL-10 played an important role in tolerance-induction process. It can be concluded that morphine tolerance slowly progressed when administered morphine effective dose was reduced during AA chronic inflammation. On the other hand, it seems that increased level of serum IL-10 may affect morphine tolerance development during inflammation.