A diencephalic circuit in rats for opioid analgesia but not positive reinforcement

Maggie W Waung,Chris O’Brien,Svetlana Bryant,Kayla A Maanum,David J Barker,Elyssa B Margolis,Marisela Morales,Thomas J Cirino,Kasra A Mansourian,Joseph R Driscoll

doi:10.1038/s41467-022-28332-6

Abstract

Mu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain.

Highlights

Mu opioid receptor (MOR) agonists are potent analgesics, and cause sedation, respiratory depression, and addiction risk
Bilateral microinjections of the MOR-selective agonist DAMGO (10 μM; 300 nL/hemisphere) into the lateral habenula (LHb) increased the average hindpaw withdrawal threshold compared to saline microinjections in the same animals, in injured animals, indicating that DAMGO reduced the mechanical hypersensitivity generated by spared nerve injury (SNI) in male rats (Fig. 1b; Results of statistical analyses including assumption testing reported in Supplemental Table 1)
Consistent with the rat literature[19], we did not observe a significant decrease in withdrawal latency to heat in the Hargreaves test after SNI compared to sham-injured controls, and DAMGO microinjections into the LHb did not alter heat withdrawal latency compared to saline in SNI or sham animals (Supplementary Fig. 1a)

Summary

Introduction

Mu opioid receptor (MOR) agonists are potent analgesics, and cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHbprojecting LPO neurons relieves the aversiveness of ongoing pain. The lateral habenula (LHb) may participate in such a circuit, as it is activated in a pain setting[1,2,3,4,5] and by other aversive states including reward omission[6] and animal models of depression[7]. Among six potential inputs to the LHb, we determined that the glutamatergic innervation from the lateral preoptic area of the hypothalamus (LPO) is both pain-responsive and most strongly inhibited by MOR activation. We show that activating MORs in this circuit in the absence of pain does not produce reinforcement, suggesting that targeting this circuit could be a significant advance in pain therapy

Methods

Results

Conclusion