A1 adenosine receptor (A1AR) is a promising drug target for neuropathic pain treatment. Some N6-substituted adenosine derivatives as A1AR agonists have shown to modulate nociception in vivo. Recently, we reported 5'-chloro-5'-deoxy-N6-(±)-endo-norbornyladenosine (5'Cl5'd-(±)-ENBA) as a very potent and highly selective human A1AR agonist with antinociceptive effects in mice.1 In this study we used mice with sciatic nerve injury (spared nerve injury, SNI) and combined behavioural, molecular and morphological approaches to assess the involvement of A1AR in neuropathic pain-associated hyperalgesia and allodynia and spinal cord gliosis and neuro-inflammation. Mechanical allodynia and thermal hyperalgesia developed 2-3 days after surgery. Morphological changes in the ipsilateral L4-L6 laminae I-II consisted of: i) increased TUNEL-positive profiles, ii) increased microglia activity, and iii) astrogliosis. Molecular expression data showed: 1) increased expression of pro-apoptotic and pro-inflammatory genes (bax, 325 ± 12%; caspase 7, 109 ± 17%; caspase 8, 133 ± 17%), 7 days after SNI. The selective A1AR agonist 5'Cl5'd-(±)-ENBA (1 mg/Kg i.p. once daily), reduced the development of thermal hyperalgesia and mechanical allodynia. This treatment in part normalized the spinal cord expression of bax, bcl-2 and caspases in SNI mice, and proved to be cytoprotective at 7 days post-SNI. This study shows that: a) allodynia and hyperalgesia developed with spinal cord glia activation, b) over-expression of pro-apoptotic or pro-inflammatory genes may be critical for maintaining gliosis in the spinal cord, and c) adenosine A1 receptor stimulation was capable to protect neuropathic mice from the observed biomolecular and morphological modifications. (1) Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393-2406.
5'-CHLORO-5'-DEOXY-N6-(±)-endo-NORBORNYLADENOSINE, A POTENT AND HIGHLY SELECTIVE HUMAN A1 ADENOSINE RECEPTOR AGONIST, PREVENTS HYPERALGESIA/ALLODYNIA AND EARLY OVER-EXPRESSION OF PRO-APOPTOTIC AND PRO-INFLAMMATORY GENES IN A MICE MODEL OF NEUROPATHIC PAIN
CAPPELLACCI, Loredana;VITA, PATRIZIA;PETRELLI, Riccardo;GRIFANTINI, Mario;
2010-01-01
Abstract
A1 adenosine receptor (A1AR) is a promising drug target for neuropathic pain treatment. Some N6-substituted adenosine derivatives as A1AR agonists have shown to modulate nociception in vivo. Recently, we reported 5'-chloro-5'-deoxy-N6-(±)-endo-norbornyladenosine (5'Cl5'd-(±)-ENBA) as a very potent and highly selective human A1AR agonist with antinociceptive effects in mice.1 In this study we used mice with sciatic nerve injury (spared nerve injury, SNI) and combined behavioural, molecular and morphological approaches to assess the involvement of A1AR in neuropathic pain-associated hyperalgesia and allodynia and spinal cord gliosis and neuro-inflammation. Mechanical allodynia and thermal hyperalgesia developed 2-3 days after surgery. Morphological changes in the ipsilateral L4-L6 laminae I-II consisted of: i) increased TUNEL-positive profiles, ii) increased microglia activity, and iii) astrogliosis. Molecular expression data showed: 1) increased expression of pro-apoptotic and pro-inflammatory genes (bax, 325 ± 12%; caspase 7, 109 ± 17%; caspase 8, 133 ± 17%), 7 days after SNI. The selective A1AR agonist 5'Cl5'd-(±)-ENBA (1 mg/Kg i.p. once daily), reduced the development of thermal hyperalgesia and mechanical allodynia. This treatment in part normalized the spinal cord expression of bax, bcl-2 and caspases in SNI mice, and proved to be cytoprotective at 7 days post-SNI. This study shows that: a) allodynia and hyperalgesia developed with spinal cord glia activation, b) over-expression of pro-apoptotic or pro-inflammatory genes may be critical for maintaining gliosis in the spinal cord, and c) adenosine A1 receptor stimulation was capable to protect neuropathic mice from the observed biomolecular and morphological modifications. (1) Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393-2406.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
