Adenylate cyclase inhibition attenuates neuropathic pain but lacks pre-emptive effects in rats

Abstract

Purpose There is evidence that cyclic adenosine monophosphate (cAMP) transduction is involved in nociceptive processing. We previously showed that intrathecal injection of an adenylate cyclase inhibitor attenuated tactile allodynia caused by partial sciatic nerve ligation (PSNL) in rats. The present study investigates the pre-emptive effects of spinal cAMP transduction on nociceptive processing in a chronic neuropathic pain model. Methods Intrathecal catheterization and PSNL were performed in male Sprague-Dawley rats. Nociceptive responses to mechanical and thermal stimuli were evaluated at the hindpaw at 2 hr and at 3, 7, and 14 days after PSNL. The pre-emptive effects of the intrathecal adenylate cyclase inhibitor, SQ22536 (0.7 lmol Á L -1 , 30 min before or after nerve ligation) were assessed. Also, the spatial and temporal expression profiles and immunoreactivity in the spinal cord of the cAMP response element binding protein (CREB) and its phosphorylated proteins (CREB-IR and p-CREB-IR) were analyzed.Results Compared with the rats treated with the vehicle, allodynia and hyperalgesia were significantly attenuated at 1-3 days by the intrathecal injection of SQ22536 performed either before or after ligation. The expression of CREB was significantly higher after ligation (P \ 0.05), but differences were not observed between groups. Intrathecal injection of SQ22536, either before or after ligation, partially reduced p-CREB-IR protein expression in comparison with the vehicle control, especially after the first 3 days (P \ 0.05). Conclusion Our results show a possible association between the increase in p-CREB and PSNL-induced neuropathic pain. However, a pre-emptive effect of adenylate cyclase inhibitor administered before surgery was not observed. RésuméObjectif Des donne´es soutiennent que la transduction de l'ade´nosine monophosphate cyclique (AMPc) est implique´e dans le traitement des signaux nociceptifs. Nous avons pre´ce´demment montre´que l'injection intrathe´cale d'un inhibiteur de l'ade´nylcyclase atte´nuait l'allodynie tactile cause´e par une ligature partielle du nerf sciatique (PSNL) chez le rat. Cette e´tude explore les effets pre´ventifs de la transduction d'AMPc rachidienne sur le traitement des signaux nociceptifs dans un mode`le de douleur neuropathique chronique. Méthode Un cathe´te´risme intrathe´cal et une PSNL ont e´te´re´alise´s sur des rats maˆles Sprague-Dawley. Les re´actions nociceptives aux stimuli me´caniques et thermiques ont e´te´e´value´es a`la patte arrie`re a`2 heures et a`3, 7 et 14 jours post-PSNL. Les effets pre´ventifs de l'inhibiteur intrathe´cal de l'ade´nylcyclase, le SQ22536, (0.7 lmolÁL -1 , 30 min avant ou apre`s la ligature du nerf) ont e´te´e´value´s. De plus, les profils d'expression spatiale et temporelle et

Mechanical allodynia

“…cAMP signalling has been primarily implicated in the development of pain hypersensitivity in an inflammatory state as many inflammatory mediators signal through G protein-coupled receptors that are coupled with G proteins that activate (Gs) adenylate cyclase, whilst other inflammatory mediators may cause an increase in intracellular calcium that activates calcium-sensitive adenylate cyclases. Pharmacological and genetic evidences also suggest a role for cAMP in the development of mechanical allodynia in rodent models of neuropathic pain [ 18 , 22 , 23 ]. For example, the development of mechanical allodynia is severely impaired in models of neuropathic pain in mice deficient for adenylate cyclase 5 [ 18 ].…”

Activation of spinal TDAG8 and its downstream PKA signaling pathway contribute to bone cancer pain in rats

“…Numerous studies have shown that activation of the spinal PKA pathway contributes to neuropathic and inflammatory pain (Wang et al. , 2006; Liou et al. , 2007, 2009; Yang et al.…”

Reduced activity of adenylyl cyclase 1 attenuates morphine induced hyperalgesia and inflammatory pain in mice

“…The lack of analgesia seen during the initial phases after CFA administration (24-48 h), could be due the deferred hypertrophy of adenylyl cyclases after tissue injury, or the delayed role of adenylyl cyclases in enhanced transcription of pro-inflammatory molecules, taking several days to manifest (Tarnawski et al, 2018). The initial change in mechanical thresholds seen at 3 h post-CFA was surprising, as a previous study failed to demonstrate a pre-emptive effect in a rodent model of neuropathic pain with adenylate cyclase inhibitor administered before injury (Liou et al, 2009). Another previous study using the AC1-specific inhibitor NB001 indicates that inhibition of hyperalgesia after CFA administration was seen 3 days after inoculation (Zhou et al, 2021).…”