Breaking barriers to novel analgesic drug development

Abstract

Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.

Figure 1. Mechanisms relevant for nociception and analgesia

There are several targets in both peripheral neurons, and in the nociceptive synapse between glia, PNS and CNS neurons in the spinal dorsal horn, that provide interventional strategies for the development of analgesics. The figure summarizes some of the major targets that have been expanded upon in the text.

Figure 2. Peripheral analgesic drug discovery targets

The peripheral terminals of primary afferent nociceptor neurons express GPCRs and various ion channels that mediate transduction of different sensory modalities, some of which have specific coupling and signaling features that offer new opportunities for novel drug classes. GPCRs can utilize both G-proteins and β-arrestins as secondary messengers and biased ligands can engage particular signaling to get increased efficacy and reduced adverse effects. GPCRs can also physically complex with other receptors leading to the formation of homomers or heteromers and also functionally interact with ion channels such as TRPV1, TRPA1, GIRKs, etc. Anti-NGF (nerve growth factor) antibodies have also been developed with the intent to alleviate certain pain modalities by blocking activation of the TrkA receptor. In addition, inhibitors for sodium and calcium channels (TRP and votage gated calcium channels) and potassium channel openers have been developed with intriguing pharmacology. We list ligands for some of these targets that are currently in analgesic clinical trials.

Figure 3. Targeting signaling between pre-synaptic nociceptors and post-synaptic neurons in the spinal dorsal horn

The central terminals of nociceptor sensory neurons synapse on neurons in the dorsal horn of the spinal cord that after processing by local circuits relay the information to the brain. The pre-synaptic nociceptor terminals deliver input generated by noxious stimuli in the periphery, inflammation and peripheral nerve injury to the post-synaptic neurons. Several of the transmission/modulation mechanisms involved represent potential analgesic targets, either by reducing excitatory or augmenting inhibitory transmission. Some of the key players – opioid, cannabinoid, NK1 and other GPCRs, along with ion channels like NMDA, AMPA, and GABA are discussed throughout the article. Another key player is the TrkA receptor which is targeted by NGF – the blocking of which has shown to produce potent analgesia. However, lack of specificity for nociceptive pathways in many cases makes on-target undesirable effects problematic.