P75-expressing elements are necessary for anti-allodynic effects of spinal clonidine and neostigmine.

Cells expressing nerve growth factor are implicated in development of hypersensitivity following nerve injury and cholinergic neurons are implicated in reduction of such hypersensitivity by alpha2-adrenergic agonists. Intrathecal injection of the cell toxin, saporin, linked to an antibody to the low-affinity nerve growth factor, p75 (192-IgG saporin), an agent which destroys cholinergic neurons in the brain, was used in the current study to further elucidate these mechanisms. Mechanical hypersensitivity was established in rats by ligation of the L5 and L6 spinal nerves. Animals were pretreated with intrathecal saline or 192-IgG saporin, and one week later received intrathecal clonidine or neostigmine. Spinal cords were removed for acetylcholine and norepinephrine analysis and for cholinergic and p75 immunohistochemistry. Treatment with 192-IgG saporin had no effect on mechanical hypersensitivity following spinal nerve ligation, but blocked the anti-hypersensitivity effects of intrathecal clonidine and neostigmine. Destruction of p75-expressing fibers in the superficial dorsal horn by 192-IgG saporin was not accompanied by changes in acetylcholine or norepinephrine content or by reduction in cholinergic neuronal number in the spinal cord dorsal horn. Unlike in the brain, 192-IgG saporin does not destroy cholinergic neurons in the spinal cord dorsal horn and cannot be used as a tool for this purpose. P75-expressing elements are not necessary for the maintenance of mechanical hyperalgesia in this model of neuropathic pain, but their destruction disrupts the targets or circuitry activated by alpha2-adrenergic and cholinergic agents to reduce hypersensitivity.