Despite rigorous research on non-opioid pain-relief drugs, morphine and other opioids still remain clinically indispensable for treating severe chronic pain. However, chronic use of these drugs could lead to two major side effects: opioid-induced hypersensitivity (OIH) and analgesic tolerance.

OIH and tolerance are the primary causes of dose escalation and limited pain control. In both human patients and animal models, OIH and tolerance mainly exhibit as either mechanical and thermal hypersensitivity, which can be further classified into hyperalgesia and allodynia (evoked by noxious and innocuous mechanical stimuli, respectively). Unfortunately, the distinct roles underlying these different substrates of OIH and tolerance have been largely ignored.

Previous studies on the mechanisms underlying OIH and tolerance did not carefully distinguish the differential mechanisms of mechanical versus thermal, as well as hyperalgesia versus allodynia. An influential study (Corder et al., Nature Medicine, 2017) showed that deleting mu-opioid receptors (MORs) from TRPV1 nociceptors attenuated both thermal and mechanical forms of morphine-induced OIH and tolerance. However, a more recent study by Du et al., (Neuroscience Bulletin, 2023) found that while the loss of peripheral MORs indeed disrupted morphine thermal tolerance, it did not prevent the development of morphine-induced mechanical OIH and tolerance.

Since peripheral MORs do not play an essential role in mediating opioid-induced mechanical forms of OIH and the corresponding analgesic tolerance, further research is needed to focus on the central mechanisms.

In a recent study by Assistant Professor Longzhen Cheng’s research group from the School of Life Sciences at the Southern University of Science and Technology (SUSTech), they have uncovered the central pathways that control opioid-induced mechanical hypersensitivity and tolerance in mice.

This work, entitled “Central control of opioid-induced mechanical hypersensitivity and tolerance in mice”, has been published in Neuron.

The researchers identified two sets of behavioral observations that prompted their current study. Firstly, pharmacological activation of MORs expressed in the parabrachial nucleus (PBN) or hypothalamus, via intra-PBN or intra-hypothalamus injections of opioids such as morphine or the MOR agonist DAMGO, paradoxically induced bilateral, morphine-resistant mechanical pain hypersensitivity, instead of providing pain relief. These observations led them to investigate whether repetitive binding of opioids to MORs in the PBN (or hypothalamus) during repeated systemic administration of opioids could be responsible for opioid-induced OIH and analgesic tolerance.

Secondly, building on their prior study (Huo et al., Cell Reports, 2023), the group highlighted that μ-opioid receptor (MOR)-expressing neurons in the lateral parabrachial nucleus (lPBN) send direct axon projections to the hypothalamic Pdyn neurons. These neurons play an essential role in controlling the laterality and duration of peripheral inflammation and nerve injury-induced mechanical pain hypersensitivity. They found that the hypothalamus-to-spinal projecting Pdyn neurons received broad innervations from multiple pain-related brain regions that covered nearly all the nuclei enriched with MORs. This suggests that chronic use of morphine could easily influence the excitability of this neural population. This finding strongly motivated them to further examine the role of these neurons in opioid-induced mechanical hypersensitivity and tolerance.

For the first time, Longzhen Cheng’s group identified a brain-to-spinal opioid pathway (lPBNMOR+→PVHDyn+→SDHKOR-GABA) that endogenously controls repetitive morphine-induced mechanical, but not thermal, hypersensitivity and analgesic tolerance. This pathway likely disrupts gate control in the dorsal horn, leading to mechanical allodynia via silencing of the gate-keeper Dyn-expressing GABAergic neurons in the spinal dorsal horn (SDHDyn-GABA). Targeting the above brain-to-spinal opioid pathways rescued repetitive systemic morphine-induced mechanical, but not thermal, forms of hypersensitivity and the corresponding analgesic tolerance.

Their studies provide a crucial new understanding into the mechanisms that underlie opioid-induced mechanical forms of OIH and analgesic tolerances. Targeting the above brain-to-spinal opioid pathways (lPBNMOR→PVHYDyn→SDHKOR-GABA→SDHDyn-GABA) could resolve opioid pain-related side effects without influencing opioid’s powerful analgesic effects. Notably, activation of MORs in the above systems does not relieve pain, as shown in the study. Since this work provides new insight into a profound medical problem of opioid pain-related side effects, it should be of both basic and clinical significance.

Ph.D. student Guangjuan Yin, Dr. Kaifang Duan (formerly a Ph.D. student), Research Assistant Professor Dong Dong, and Dr. Feng Du (formerly a Ph.D. student) from the Cheng laboratory at SUSTech are the co-first authors of the paper. Assistant Professor Longzhen Cheng is the corresponding author.

Paper link: https://www.cell.com/neuron/fulltext/S0896-6273(24)00662-7

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