Immunostained fluorescence microscopy image of a neuronal activation biomarker (phosphorylated extracellular regulated kinase, red) that increases in mouse spinal cord neurons (green) during opioid receptor inverse agonism. Inflammation or injury to the skin causes μ-opioid receptors to become constitutively active, which leads to long-term relief from chronic pain, but at the expense of endogenous opioid dependence.
General Model and Hypothesis. Our conceptual model of the transition from acute to chronic pain is based on the delicate balance between latent pain sensitization (LS) and endogenous analgesia that develops after painful tissue injury (Taylor and Corder, 2014). First, severe tissue injury triggers the development of central sensitization and acute pain (red line). Second, the spinal cord establishes compensatory analgesia, µ-opioid receptor constitutive activity (Blue line, MORCA) which then enables pain resolution (red line). But third, over time, the body becomes dependent on MORCA, leading to chronic pain vulnerability in the form of LS that is driven by glutamate receptors and cAMP-mediated signalling (Green line). The final result is a silent insidious state characterized by the escalation of these opposing excitatory and inhibitory influences on pain transmission. If this balance is perturbed, e.g. upon inverse agonist blockade of MORCA (dotted line), then LS can be visualized as pain reinstatement. Chronic pain syndromes may result from a failure in constitutive signalling of spinal MORs and a loss of endogenous analgesic control -- perhaps caused by stress. Our long-term goal is to alleviate chronic pain by either: a) facilitating endogenous opioid analgesia, thus restricting LS within a state of remission; or b) extinguishing LS altogether, for example with a selective AC1 or Epac1 inhibitor.
In a mouse with a history of injury that later received the opioid receptor antagonist naltrexone (NTX), physical dependence to mu-opioid receptor constitutive activity is manifested as endogenous withdrawal (jumping and paw tremor). Neither vehicle nor naltrexone methobromide (NMB), an opioid receptor blocker that does not cross the blood-brain-barrier, precipitated withdrawal. Credit: Greg Corder and Brad Taylor
Calcium imaging in spinal cord tissue taken at 21 days post-injury demonstrates an enhanced response to the excitatory neurotransmitter glutamate following naltrexone (NTX) treatment, suggesting that blocking mu-opioid receptor constitutive activity "releases the brakes" on neuronal activity and promotes pain hypersensitivity.
Our paper underlying this working hypothesis (Corder et al, 2013) was featured on the cover of Science, was accompanied by an Editor’s cover story, was the focus of several news stories (e.g. The Scientist, Businessweek, Nature Medicine, Pain Research Forum), and was later announced in 2014 as the annual “Top Science Advance in Pain Research” by the NIH Interagency Pain Research Coordinating Committee.
MedicalXPress
Pain Research Forum
Spoonful of Medicine (Nature Medicine Blog)
As initially reported in Science (Corder et al., Science 341: 1394-1399, 2013), the Taylor laboratory discovered that tissue inflammation, peripheral nerve injury, or surgical incision produces a latent sensitization (LS) of chronic pain that is tonically opposed by mu opioid receptor constitutive activity (MORCA) in the spinal cord and brain. They found that blockade of MORCA reinstated hyperalgesia, affective pain, and molecular and neurophysiological markers of spinal pain transmission – even when delivered more than a year after the induction and resolution of early acute pain. They also reported that LS can develop in humans, further implicating LS as an explanation for the episodic nature of chronic pain.
Recently, the basic science of their work has extended to the kappa opioid receptor and is now combining a variety of approaches, including fluorescent in situ hybridization, RNA sequencing, slice electrophysiology, fiber photometry, and GCaMP imaging, together with behavioral models of chronic pain, to determine whether MORCA in the spinal cord and brain (amygdala and rostral ventral medulla [RVM]) constrains chronic pain within a state of remission. They are thinking ahead to renew their R01 (2016-2022), with the goal to better understand how MORCA synergizes with other pain inhibitory GPCRs (including neuropeptide Y1 and kappa opioid receptors) on MOR- and KOR-expressing neurons in the spinal cord and RVM. With this work, their lab hopes to ultimately generate clinical trials to either: a) facilitate endogenous opioid receptor analgesia, thus restricting chronic pain within a state of remission; or b) extinguish chronic pain altogether.
PI, NIH/NIDA RO1 DA037621-01A1, 08/15/15-06/30/21: “Long-term activation of spinal opioid analgesia after inflammation.”