Adrenergic Regulation of Spinal Neurons in Chronic Pain: Does the noradrenergic descending pain control system facilitate pain due to spinal reorganization under chronic pain conditions in mice?

• Applicant: Dr. Silke Hirsch
• Subject Area: Experimental and Theoretical Network Neuroscience ; Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 439922175

Chronic pain is one of the most difficult to endure and to treat conditions. Mechanisms are not well understood. Yet, the adrenergic system seems to influence many chronic pain syndromes. Studying the adrenergic regulation of spinal neurons in neuropathic mice via electrophysiologically recording from spinal wide dynamic range (WDR) cells in vivo with receptive fields in the hind paw shall answer the following question: Can a, presumably neuropathy-induced, spinal upregulation of excitatory α1 adrenergic receptors drive the descending inhibitory system, which usually acts via predominating inhibitory α2 adrenergic receptors, towards facilitation in spinal neuronal circuits? Single WDR neurons will be recorded extracellularly and their activity will be monitored before, during and after electrical and optogenetic stimulation of locus coeruleus. Locus coeruleus activity plays a key role in descending inhibition of painful stimuli in the spinal cord. Comparably, evoked spinal WDR neuronal activity will be recorded before and after inhibition of the descending fibres via cooling of spinal cord proximal to the recording site. Thereby both effects - of activating and of inhibiting the descending system - will be compared. Spinal blockade of alpha1- or alpha2-adrenoceptors by intrathecal application of terazosin or atipamezole respectively will clarify the impact of these receptor subtypes on the spinal neuronal activity. Histological and molecular analyses will be used for receptor quantification in the spinal cord. Additionally, the spinal cells of the dorsal horn α adrenoceptors are located on shall be identified using cell-type and pathway-specific molecular markers. In neuropathy, the noradrenergic system seems to fail, hypothetically due to a switch in the α1/α2 ratio of the adrenergic receptor population in the spinal circuitry. This hypothesis will be tested electrophysiologically and pharmacologically in the well-studied murine neuropathic pain model PNL (partial nerve ligation) and in bone-fractured mice, the latter as a model of complex regional pain syndrome, in which the adrenergic system is often found to be disturbed. A better understanding of the pathological mechanisms may result in a better therapy.

• DFG Programme: Research Grants