Updates & Features
TRP ion channels and analgesia – targeting cellular environmental sensors
June 2018
PainSolve Editorial Team
Understanding nociception: the role of ion channels in detecting physical stimuli
Since the cloning of the capsaicin receptor, now known as TRPV1 (Transient Receptor Potential Vanilloid 1) in 1997, much progress has been made in understanding the role of this and related TRP ion channels as cellular sensors involved in nociception (Kaneko 2014). Currently, 28 TRP ion channels have been identified (Huang 2017), which are divided into six subfamilies on the basis of sequence homology (Kaneko 2014). Eight members from three subfamilies have been reported to be involved in nociception (table 1) (Gonzalez-Ramirez 2017).
| TRP ion channel subfamily | Members involved in nociception | Associated pain modalities |
| TRPC (Canonical) | – | – |
| TRPV (Vanilloid) | TRPV1 | Inflammatory pain, neuropathic pain, visceral pain |
| TRPV2 | Inflammatory pain | |
| TRPV3 | Nociceptive pain, inflammatory pain | |
| TRPV4 | Mechanically-evoked pain, inflammatory pain, neuropathic pain, visceral pain, headache | |
| TRPM (Melastatin) | TRPM2 | Inflammatory pain |
| TRPM3 | Neurogenic pain | |
| TRPM8 | Cold hypersensitivity, neuropathic pain | |
| TRPP (Polycystin) | – | – |
| TRPML (Mucolipin) | – | – |
| TRPA (Ankyrin) | TRPA1 | Cold hypersensitivity, nociceptive pain, inflammatory pain, mechanical hyperalgesia, inherited episodic pain syndrome |
–: None to date.
All the TRP channels known to participate in nociception are ligand-gated cationic channels. These channels are expressed by excitable membranes, such as those in primary sensory neurons (PSNs). When activated, TRP channels become permeable to all major cations (Na+, K+, Ca2+) in the extra- and intracellular fluids. This depolarises the membrane and increases the probability of action potential generation, which induces excitation in postsynaptic neurons. Nociceptive neurons send signals from the periphery, through the afferent fibers, to the visceral, trigeminal, and somatic regions, and also connect the spinal cord to the brain, thus serving as mediators in painful stimulus transmission between the central and peripheral nervous systems (Gonzalez-Ramirez 2017). Selective and specific blockade of nociception-related TRP channels should reduce PSN excitation, thereby, providing significant pain relief (Sousa-Valente 2014).
Insights from early TRP channel modulators
TRPV1 is the most well-characterized TRP channel and can be activated by temperature (~42°C), pH, and a variety of endogenous and exogenous compounds (Gonzalez-Ramirez 2017). Many compounds have been developed to modulate TRPV1 activity (Carnevale 2016). However, early trials of TRPV1 antagonists revealed that they can cause hyperthermia and accidental burns in susceptible patients (by elevating the threshold for detection of noxious heat) (Gonzalez-Ramirez 2017). Consequently, several TRPV1 antagonists such as AMG-517 and AZD1386 were discontinued.
Investigational TRP channel modulators and future directions
Burn prevention measures such as prestudy counseling and provision of temperature-testing devices were employed in a phase I trial of mavatrep, a novel TRPV1 antagonist (Manitpisitkul 2016). An efficacy signal was observed in participants with osteoarthritis (OA) pain (Manitpisitkul 2018). Preliminary results from a phase II study of NEO6860, another TRPV1 antagonist, demonstrated that NEO6860 has an analgesic effect without affecting core body temperature or noxious heat perception in patients with severe OA pain (Neomed 2017).
| Type of molecule | Agent (company) | Indication | Trial phase (ClinicalTrials.gov Identifier) | Status |
| TRPV1 antagonist | Mavatrep/JNJ-39439335 (Janssen) | Chronic pain | Phase I (NCT00933582) | Completed |
| TRPV1 antagonist | NEO6860 (Neomed Institute) | OA pain, Neuropathic pain, Visceral pain | Phase II (NCT02712957) | Completed |
| TRPV1 agonist | Qutenza/capsaicin (Acorda; Grunenthal) | Peripheral neuropathic pain | Approved by FDA and EMA in 2009 | |
| TRPV1 agonist | Resiniferatoxin (Sorrento Therapeutics) | Neurogenic inflammatory pain | Phase I (NCT00804154) | Recruiting |
| TRPV3 inhibitor | GRC-15300 (Glenmark Pharmaceuticals; Sanofi) | Neuropathic pain | Phase II (NCT01463397) | Completed; development terminated in 2014 |
| TRPA1 antagonist | GRC-17536 (Glenmark Pharmaceuticals) | Neuropathic pain | Phase II (NCT01726413) | Completed |
Nonsteroidal anti-inflammatory drugs (NSAIDs) have the potential for serous cardiovascular and gastrointestinal side effects and opioids are associated with respiratory depression. It is anticipated that TRP channel modulators will provide an alternative treatment option to NSAIDs and opioids (Dai 2016).
Grünenthal, the KU Leuven’s Centre for Drug Design and Discovery (CD3) and the Laboratory of Ion Channel Research (LICR) recently announced that they have entered into a research collaboration to develop an innovative non-opioid pain treatment (KU Leuven 2018).
References
- Carnevale V, Rohacs T. Pharmaceuticals (Basel). 2016; 9: pii: E52
- Dai Y. Semin Immunopathol. 2016; 38: 277-91
- González-Ramírez R, et al. Chapter 8. TRP channels and pain. In: Emir TLR, editor. Neurobiology of TRP Channels. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2017
- Huang S, Szallasi A. Pharmaceuticals (Basel). 2017; 10: pii: E64
- Kaneko Y, Szallasi A. Br J Pharmacol. 2014; 171: 2474–507
- KU Leuven. Grünenthal and KU Leuven join forces to develop an innovative non-opioid pain treatment. Available at:https://lrd.kuleuven.be/en/news/grunenthal-and-ku-leuven-join-forces-to-develop-an-innovative-non-opioid-pain-treatment (accessed 06 June 2018)
- Manitpisitkul P, et al. Pain Rep. 2016; 1: e576.
- Manitpisitkul P, et al. Scand J Pain. 2018; 18: 151–164
- Moran MM, Szallasi A. Br J Pharmacol. 2017; doi: 10.1111/bph.14044
- Neomed Institute. NEO6860 Transient receptor potential vanilloid type 1 (TRPV1) antagonist. Available at: http://neomed.ca/en/projects/neo6860/ (accessed 06 June 2018)
- Sousa-Valente J, et al. Br J Pharmacol. 2014; 171: 2508–27