Dynamic Role of Intra-Locus Coeruleus Mu Opioid Receptors in Nociception

Abstract

<b>Abstract ID 24694</b> <b>Poster Board 346</b> The locus coeruleus (LC) provides the largest noradrenergic innervation to the central nervous system and is a major node in pain neural circuitry. LC noradrenergic neurons directly project to the dorsal horn of the spinal cord. It is through these direct spinal projections LC neurons leverage their antinociceptive influence locally via alpha-2 adrenoreceptor activation to inhibit nociceptive afferents. The LC responds to noxious stimuli with a shift from low tonic to phasic activation and stimulation of the LC has been shown to be antinociceptive. Paradoxically, however, here we show that optogenetic inhibition of LC activity is also acutely antinociceptive - a finding opposite of the canonical role of LC neurons in nociceptive processing. To determine the mechanistic underpinnings of this novel phenomenon, we focused on the dense concentration of mu opioid receptors (MORs) in the LC. Intra-LC MORs have been implicated in several biological processes including, neuropathic pain and stress. Literature suggests intra-LC MORs may be particularly critical for LC-mediated changes in nociception. Pharmacological activation of these MORs has been shown to dose-dependently inhibit LC neuronal activity and promote antinociception. To determine the role of intra-LC MORs in nociceptive processing we developed a MOR conditional knockout (cKO) mouse line. In these mice, MORs are conditionally deleted in cells where MORs are coexpressed with the critical enzyme required to produce norepinephrine (dopamine beta hydroxylase). Furthermore, conditional deletion of MORs in dopamine beta hydroxylase cells, decreased nociceptive thresholds at baseline. To determine whether intra-LC MORs are sufficient to return lower withdrawal thresholds in MOR cKO mice back to baseline, we cell-type selectively rescued MOR function in these mice using a light sensitive MOR, opto-MOR. Finally, to determine whether the LC’s pronociceptive function is conserved in neuropathic pain states, we found optogenetic inhibition of the LC 1-week post spared nerve injury resulted in contralateral allodynia. Interestingly, however, inhibition 4 weeks after injury became ipsilaterally antinociceptive suggesting LC activity shifted from pronociceptive to analgesic when neuropathic injury became more chronic. Together, our results suggest the LC controls basal nociception in a MOR-dependent manner that becomes highly dynamic in neuropathic pain states.