The role of the spinal cyclooxygenase (COX) for incisional pain in rats at different developmental stages

Abstract

Background Cyclooxygenase enzymes (COX)‐1 and COX‐2 are important targets for pain relief after surgery, but the spinal contribution of both isoforms is still unclear, e.g., from a developmental point of view. Here, we studied changes of spinal COX‐1 and COX‐2 expression and their functional relevance in rats of different ages for pain‐related behaviour after incision. Methods Mechanical paw withdrawal thresholds (PWT) were assessed before and after incision and after intrathecal administration (IT) of SC‐560 (COX‐1 inhibitor) or NS‐398 (COX‐2 inhibitor) in rats aged 5, 14 and 28 days (P5, P14, P28). Furthermore, spinal expressions of COX m‐RNA and proteins were investigated. Results In P5 rats, only IT‐administered NS‐398 but not SC‐560 significantly reversed the decreased PWT after incision. In P14 rats, none of the substance modified PWT, and in P28 rats, only SC‐560 increased PWT. Spinal COX‐2 mRNA and protein were increased in P5 but not in P14 and P28 rats after incision. Whereas COX‐2 is located in spinal neurons, COX‐1 is mainly found in spinal microglia cells. Conclusion Our results demonstrate a possible developmental transition from COX‐2 to COX‐1 activation. Whereas in adult rats spinal COX‐1 but not COX‐2 is involved in pain‐related behaviour after incision, it seems opposite in P5 rats. Interestingly, in P14, neither COX‐1 nor COX‐2 seems to play a role. This switch may relate to altered neuronal/microglia activation. Our findings indicate specific mechanisms to pain after incision that are age‐dependent and may guide further research improving paediatric pain management. Significance Postoperative pain in pediatric patients after surgery is still poorly controlled; this might contribute to long‐lasting alteration in the nociceptive system and prolonged chronic pain. Here we show a possible developmental switch in the COX‐dependent pathway for nociceptive spinal transmission that may explain why pain management in young children needs to be related to age‐dependent mechanisms.

Spinal GABA transporter 1 contributes to evoked-pain related behavior but not resting pain after incision injury

“…For example, in previous neuropathic pain studies, many other examples for time-specific changes in signaling have been reported (Cobos et al, 2018;Segelcke et al, 2021a). In an earlier study, we identified a developmental variation in the function of cyclooxygenase 2 in postoperative pain (Segelcke et al, 2020), further reinforcing the link of function in development of pain disease. Here, for example, we described increased GAT-1 expression during the early phase 4 h following incision (initiation phase), but not at later time points (POD1, POD3 and POD5) during the maintenance phase, which would have been missed if only later time points had been investigated.…”

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“…The differences in the effect of ropivacaine between the studies may be due to the different method of drug administration [16,[37][38][39][40]. However, strain differences (domestic pigs vs. minipigs) [41], sex [42], and age [43,44] may also affect the action of ropivacaine.…”

Transcriptional Alterations of Mouse Trigeminal Ganglion Neurons Following Orofacial Inflammation Revealed by Single-Cell Analysis

“…Peripheral nerve injury induced by axotomy and TG extraction during our experiments do not rule out the transcriptional alterations of neuroregeneration and neuroprotection genes in neuron. Moreover, the hub genes, such as Actb , Gsk3b , and mt-Co1 , were identified, which are closely correlated with pain development ( Liu et al, 2017 ; Noori et al, 2020 ; Segelcke et al, 2020 ). And the roles and mechanisms of several potential novel targets in orofacial inflammatory pain, such as Scn7a and Zbtb20 in PEP1, Rgs7bp in PEP2, and Bhlha9 in cLTMR, require further exploration.…”