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Chronicling changes in the somatosensory neurons after peripheral nerve injury.

ABSTRACT: Current drug discovery efforts focus on identifying lead compounds acting on a molecular target associated with an established pathological state. Concerted molecular changes that occur in specific cell types during disease progression have generally not been identified. Here, we used constellation pharmacology to investigate rat dorsal root ganglion neurons using two models of peripheral nerve injury: chronic constriction injury (CCI) and spinal nerve ligation (SNL). In these well-established models of neuropathic pain, we show that the onset of chronic pain is accompanied by a dramatic, previously unreported increase in the number of bradykinin-responsive neurons, with larger increases observed after SNL relative to CCI. To define the neurons with altered expression, we charted the temporal course of molecular changes following 1, 3, 6, and 14 d after SNL injury and demonstrated that specific molecular changes have different time courses during the progression to a pain state. In particular, ATP receptors up-regulated on day 1 postinjury, whereas the increase in bradykinin receptors was gradual after day 3 postinjury. We specifically tracked changes in two subsets of neurons: peptidergic and nonpeptidergic nociceptors. Significant increases occurred in ATP responses in nAChR-expressing isolectin B4+ nonpeptidergic neurons 1 d postinjury, whereas peptidergic neurons did not display any significant change. We propose that remodeling of ion channels and receptors occurs in a concerted and cell-specific manner, resulting in the appearance of bradykinin-responsive neuronal subclasses that are relevant to chronic pain.

SUBMITTER: Raghuraman S

PROVIDER: S-EPMC7584894 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The sigma-1 receptor (?1R), an endoplasmic reticulum chaperone protein, is widely distributed and regulates numerous intracellular processes in neurons. Nerve injury alters the structure and function of axotomized dorsal root ganglion (DRG) neurons, contributing to the development of pain. The ?1R is enriched in the spinal cord and modulates pain after peripheral nerve injury. However, ?1R expression in the DRG has not been studied. We therefore characterized ?1R expression in DRGs at baseline and following spinal nerve ligation (SNL) in rats.Immunohistochemical (IHC) studies in DRG sections show ?1R in both neuronal somata and satellite glial cells. The punctate distribution of ?1R in the neuronal cytoplasm suggests expression in the endoplasmic reticulum. When classified by neuronal size, large neurons (>1300 ?m) showed higher levels of ?1R staining than other groups (700-1300 ?m, <700 ?m). Comparing ?1R expression in neuronal groups characterized by expression of calcitonin gene-related peptide (CGRP), isolectin-B4 (IB4) and neurofilament-200 (NF-200), we found ?1R expression in all three neuronal subpopulations, with highest levels of ?1R expression in the NF-200 group. After SNL, lysates from L5 DRGs that contains axotomized neurons showed decreased ?1R protein but unaffected transcript level, compared with Control DRGs. IHC images also showed decreased ?1R protein expression, in SNL L5 DRGs, and to a lesser extent in the neighboring SNL L4 DRGs. Neurons labeled by CGRP and NF-200 showed decreased ?1R expression in L5 and, to a lesser extent, L4 DRGs. In IB4-labeled neurons, ?1R expression decreased only in axotomized L5 DRGs. Satellite cells also showed decreased ?1R expression in L5 DRGs after SNL.Our data show that ?1R is present in both sensory neurons and satellite cells in rat DRGs. Expression of ?1R is down-regulated in axotomized neurons as well as in their accompanying satellite glial cells, while neighboring uninjured neurons show a lesser down-regulation. Therefore, elevated ?1R expression in neuropathic pain is not an explanation for pain relief after ?1R blockade. This implies that increased levels of endogenous ?1R agonists may play a role, and diminished neuroprotection from loss of glial ?1R may be a contributing factor.

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Chronicling changes in the somatosensory neurons after peripheral nerve injury.

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