Knock down of the alpha 5 nicotinic acetylcholine receptor in spinal nerve-ligated rats alleviates mechanical allodynia.
Nicotinic acetylcholine receptor (nAChR) agonists are known to alleviate neuropathic and inflammatory pain via activation of a heterogeneous population of receptors. However, the function of nAChRs in the maintenance of neuropathic pain is not known. Spinal nerve ligation (SNL) increases the spinal expression of the alpha5 nAChR subunit ipsilateral to injury. The alpha5 subunit is unique because it modifies numerous characteristics of existing functional nAChRs, but it does not form functional nAChRs when expressed alone or with beta nicotinic subunits. Because there are no alpha5 subunit selective ligands, we used antisense oligonucleotides (ODNs) to assess the contribution of the alpha5 subunit to the maintenance of mechanical allodynia following SNL. Intrathecal antisense oligonucleotides were administered to SNL rats after the development of mechanical allodynia (10-12 days post-SNL). I.t. antisense specifically reduced alpha5 immunoreactivity (alpha5-IR) by 50-70% in the outer laminae of the dorsal horn and moderately alleviated mechanical allodynia. Furthermore, using the phosphorylation of cAMP response element-binding protein (pCREB) as a general marker of neuronal activation, a significant increase in pCREB immunoreactivity was observed in SNL rats. Treatment of SNL rats with alpha5-antisense significantly reduced pCREB immunoreactivity. These results suggest that the increased expression of the alpha5 nAChR subunit following SNL contributes to spinal CREB phosphorylation and the maintenance of mechanical allodynia.
Vincler
Michelle A
MA
Department of Anesthesiology and Center for the Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009, USA. mvincler@wfubmc.edu
Eisenach
James C
JC
D000818:Animals; D008026:Ligation; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010146:Pain / Q000235:genetics*; D010147:Pain Measurement / Q000379:methods*; D010766:Phosphorylation; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000172:deficiency* / Q000235:genetics*; D013127:Spinal Nerves / Q000378:metabolism*
C499978:Chrna5 protein, rat; D011978:Receptors, Nicotinic