We have, in the past 15 years, examined the mechanisms of alpha2-adrenoceptor mediated analgesia in the spinal cord and their plasticity following nerve injury. We shift our focus in this application to alpha2- adrenoceptors on peripheral afferents, due to two clinical observations. First, injection of clonidine at the site of nerve injury causes a delayed onset, long-lasting analgesia in patients and in animals. Preliminary data show this is an effect on alpha2-adrenoceptors, likely on macrophages, and results in altered phenotype of injured afferents. We will investigate the mechanisms of action of alpha2-adrenoceptors at the site of nerve injury, specifically: 1. Determine by what mechanisms alpha2-AR stimulation at the site of nerve injury affects the balance between macrophages with a pro-inflammatory phenotype, which release factors, which drive neuronal hypersensitivity (TNFalpha, IL-1beta, and NGF), and those with an anti-inflammatory phenotype. 2. Determine the consequences of alpha2-AR stimulation at the site of nerve injury on the phenotype of injured afferents, focusing on functional Na+ channels in the cell body and peripheral nerve. The second clinical observation is that epidural injection of clonidine does not cause pain in patients with peripheral nerve injury, and often causes analgesia. Yet, studies in animals convincingly demonstrate novel expression of excitatory alpha2-adrenoceptors on injured afferents and nociceptors. Preliminary studies show that nerve injury leads to increased alpha2-adrenoceptor expression, and alpha2-adrenoceptor mediated inhibition of electrically stimulated cell bodies, and increased clonidine-induced release by afferents of the inhibitory neurotransmitter, somatostatin. To further investigate mechanisms of these effects, we will: 3. Determine the role of alpha-AR types and subtypes underlying reduced response to stimulation in injured DRG cell bodies, the classes of cells affected, and the indirect role of SST in this inhibition.
|Hayashida, Ken-Ichiro; Clayton, Bridgette A; Johnson, James E et al. (2008) Brain derived nerve growth factor induces spinal noradrenergic fiber sprouting and enhances clonidine analgesia following nerve injury in rats. Pain 136:348-55|
|Romero-Sandoval, Alfonso; Eisenach, James C (2007) Clonidine reduces hypersensitivity and alters the balance of pro- and anti-inflammatory leukocytes after local injection at the site of inflammatory neuritis. Brain Behav Immun 21:569-80|