Abstract
Peripheral nerve injury results in dramatic upregulation in pituitary adenylate cyclase activating polypeptide (PACAP) expression in adult rat dorsal root ganglia and spinal motor neurons mirroring that described for the neurotrophin brain derived neurotrophic factor (BDNF). Thus, we posited that injury-associated alterations in BDNF expression regulate the changes in PACAP expression observed in the injured neurons. The role of endogenous BDNF in induction and/or maintenance of PACAP mRNA expression in injured adult rat motor and sensory neurons was examined by intrathecally infusing or intraperitoneally injecting BDNF-specific antibodies or control IgGs immediately at the time of L4-L6 spinal nerve injury, or in a delayed fashion one week later for 3 days followed by analysis of impact on PACAP expression. PACAP mRNA in injured lumbar sensory and motor neurons was detected using in situ hybridization, allowing quantification of relative changes between experimental groups, with ATF-3 immunofluorescence serving to identify the injured subpopulation of motor neurons. Both the incidence and level of PACAP mRNA expression were dramatically reduced in injured sensory and motor neurons in response to immediate intrathecal anti-BDNF treatment. In contrast, neither intraperitoneal injections nor delayed intrathecal infusions of anti-BDNF had any discernible impact on PACAP expression. This impact on PACAP expression in response to BDNF immunoneutralization in DRG was confirmed using qRT-PCR or by using BDNF selective siRNAs to reduce neuronal BDNF expression. Collectively, our findings support that endogenous injury-associated BDNF expression is critically involved in induction, but not maintenance, of injury-associated PACAP expression in sensory and motor neurons.
Highlights
The peptidergic phenotype in sensory and motor neurons is dramatically changed in response to nerve injury and is implicated in the neurons’ capability to survive and regenerate
DRG neurons are immunoreactive for pituitary adenylate cyclase activating polypeptide (PACAP) and express PACAP mRNA, whereas in the spinal cord, PACAP immunoreactivity has been found in nerve fibers in the superficial laminae of the dorsal horn, dorso-laterally to the central canal [12,13,14,15,16,17], and in fibers and neurons in the intermediolateral column (IML) [14,18]
We and others have shown that the neuropeptide PACAP is markedly upregulated in sensory and motor neurons, in response to nerve transection, peripheral inflammation and compression injury [13,15,19,21,22,25,51], where it is believed to subserve roles in modulation of nociception [1,2,3,4,5,6], survival and regeneration of injured neurons [7,8,9,10,11]
Summary
The peptidergic phenotype in sensory and motor neurons is dramatically changed in response to nerve injury and is implicated in the neurons’ capability to survive and regenerate. Roughly a fifth of the rat DRG neurons (primarily nerve cell bodies of smaller diameter) express mRNA or show immunoreactivity for PACAP, whereas very few spinal cord ventral horn neurons show PACAP expression [12,13,14,15,16,20] This expression is highly plastic and changes in response to nerve lesion or inflammation. In the DRG, a phenotypic switch is observed whereby expression is induced primarily in medium-large diameter neurons, while expression in the small size neurons declines after sciatic or spinal nerve transection [13,15,16,21] This contrasts with what is observed in response to a compression injury where an upregulation in PACAP expression is observed across all size ranges of DRG neurons [22]
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