New Possibilities for Pain Treatment | Pain Research Forum – From the annual Pain Therapeutics Summit
The following report summarizes select presentations from the Boston meeting on novel pain targets and drug molecules.
Here are the topics that were presented:
- Angiotensin II type 2 receptor antagonist gives first results
- Glia-targeted therapy tested in dogs
- Targeting TRPV1
- Trigeminal treatments
- Latching onto lipids
- Finally, an old target made new
Angiotensin II type 2 receptor antagonist gives first results
Inhibitors of the vasoconstrictive angiotensin II type 1 receptor (AT1) are used widely to treat high blood pressure and heart failure. But researchers have also discovered that another member of the same receptor family, the AT2 receptor, plays important roles in peripheral pain-sensing neurons
Spinifex Pharmaceuticals, Melbourne, Australia, presented results from a Phase 2 trial of the company’s AT2 inhibitor, EMA401, in patients with post-herpetic neuralgia
Spinifex is now testing EMA401 in a Phase 2 open-label study in patients with chemotherapy-induced painful neuropathy (Australian New Zealand Clinical Trials Registry) and is planning clinical trials in a range of chronic pain conditions, including diabetic neuropathy and pain due to osteoarthritis.
Glia-targeted therapy tested in dogs
In another talk, Linda Watkins, University of Colorado, Boulder, US, presented data on a glia-targeted therapy from Xalud Therapeutics, a company she founded and where she is currently chief scientific officer. The company, based in Boulder and San Francisco, US, is developing a non-viral interleukin-10 (IL-10) gene therapy.
Studies in animals have shown that in pathological pain states, activated glia in the spinal cord release proinflammatory products that drive pain and undercut opioid analgesia, and also create dependence and other undesirable effects
IL-10, an endogenous anti-inflammatory cytokine, broadly counteracts those effects—it is “nature’s own negative feedback on neuroinflammation,”
Watkins presented animal data showing that a single intrathecal injection of XT-101 reverses mechanical hypersensitivity for up to three months in rodent models of injury- and chemotherapy-induced nerve damage.
Selectively targeting primary afferent neurons was also the focus of a talk by Michael Iadarola, National Institutes of Health
Iadarola and his team are working on agents that activate the transient receptor potential channel TRPV1. The channel is the target of multiple therapeutic strategies, including both agonists and antagonists
Paradoxically, while opening TRPV1 temporarily causes pain, keeping the channel open long enough can reduce pain. The prolonged activation of TRPV1 lets in a toxic flood of calcium ions that damage the axons of TRPV1-containing nociceptors or even kills the cells
To wedge TRPV1 open, Iadarola is using resiniferatoxin (RTX), a highly selective, ultra-potent capsaicin analog and TRPV1 agonist from resin spurge plants. In previous studies in pet dogs with pain from bone cancer, intrathecal RTX produced dramatic improvement in comfort
lasmiditan, a 5HT1F subtype-selective serotonin receptor agonist being developed as an acute therapy for migraine
Lasmiditan selectively activates 5HT1F receptors, which are not widely expressed in blood vessels but are expressed on neurons in the trigeminal ganglia and brain.
Lasmiditan has shown significant migraine pain relief in two Phase 2 studies in migraine
work on nasal oxytocin as a new therapy for head pain conditions that involve the trigeminal nerves.
The trigeminal neurons that signal pain in the face and head express oxytocin receptors, especially during painful inflammation. As a result, Yeomans reported, oxytocin has proven to be highly analgesic in rat models of head pain and inflammation.
Yeomans’ clinical colleagues have tested that theory by giving nasal oxytocin off-label to patients with a variety of intractable head pain conditions, and in 22 of 27 cases, he said, patients experienced complete or near complete relief.
in a small number of patients with trigeminal neuralgia who were treated with TI-001 in an open trial, all experienced pain relief.
Latching onto lipids
drug development effort focused not on proteins, but on the pain-promoting lipid lysophosphatidic acid (LPA). Lpath creates monoclonal antibodies that specifically and tightly latch onto and neutralize bioactive lipids.
Given the multiple receptors through which LPA acts, Sabbadini said that targeting LPA itself, rather than its receptors, is the better strategy for stopping painful signaling.
Lpath is now manufacturing the antibody and beginning toxicity studies, Sabbadini said, in anticipation of clinical trials.
Finally, an old target made new
made the case for a still untapped potential in the opioid receptors. Each opioid receptor gene produces not one receptor, but a plethora of different splice variants that may have different downstream signaling properties. If pharmacologists could identify and target just those variants involved in modulating pain, they might effect analgesia without side effects.
Pasternak focused on a set of μ (mu) opioid receptor (MOR) variants that lack the N-terminal transmembrane (TM) domain, producing receptors with only six (rather than the usual seven) TM segments.
his lab is now synthesizing compounds with increased activity and selectivity for 6TM receptors.