Research Topic

Application of Plant Secondary Metabolites to Pain Neuromodulation

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About this Research Topic

The importance of natural products and their metabolites in the treatment of pain and other diseases has been recognized by contemporary science, and a range of medications currently used in the clinic were indeed initially developed from natural products including medicinal plants.

Historically, ...

The importance of natural products and their metabolites in the treatment of pain and other diseases has been recognized by contemporary science, and a range of medications currently used in the clinic were indeed initially developed from natural products including medicinal plants.

Historically, the mark of obtaining bioactive compounds with analgesic potential occurred in the 19th century when the first analgesic drugs obtained from medicinal plants were marketed. These included especially the opioids, such as morphine extracted from papaver (Papaver somniferum) and acetylsalicylic acid, which was synthesized from salicylic acid extracted from willow bark (Salix spp.).

After almost two centuries, new analgesic compounds have been extracted from natural products, for example capsaicin obtained from pepper (Capsicum annuum), the peptide ziconotide extracted from the marine mollusc Conus magus, and cannabinoid compounds extracted from Cannabis sativa (tetrahydrocannabinol, cannabidiol and others).

In addition to the diversity of their chemical constituents, natural products have a range of pharmacological targets that make them potent analgesic compounds. In fact, a large part of these compounds is able to promote the modulation of several neurotransmission systems, such as opioid, cannabinoid and purinergic, as well as voltage-sensitive ion channels including transient receptor potential (TRP) channels and acid-sensing ion channels (ASICs). Besides, these compounds are normally important modulators of inflammatory mediators release and redox imbalance. Even in case of rheumatoid arthritis, neuropathy, focus on the redox imbalance as well as hyaluronidase inhibition are also the important factors, which are being considered by the researchers worldwide. In this context, natural products like nuciferoic acid plays a very important role in controlling hyaluronidase enzyme.

Thus, natural products are able to act in several areas of the nervous system, such as nociceptive fibres, spinal cord and encephalic nuclei of the descending pain modulatory pathway, which contribute to decrease of nociceptive stimulus perception, modulate the conduction pathways and activate descending pain control circuits. In fact, several research groups around the world have demonstrated that these compounds are able to modulate the complex neurobiology of pain transmission in the context of several painful conditions, such as fibromyalgia, cancer pain, neuropathic pain, rheumatoid arthritis, among others. The lack of an effective treatment for many of these disorders, constantly stimulates the development of research in this area.

However, challenges like the precise knowledge of their neuropharmacological effects and their mechanisms of action, stability, bioavailability and safety, as well as the scarcity of clinical trials, still represent obstacles to the advancement of this research field.

This Research Topic therefore aims to provide significant evidence of well-defined bioactive compounds or plant extracts obtained from medicinal plants and its potential analgesic effects through pain neuromodulation, supported with clear molecular targets and mechanisms of actions illustrated through a broad and translational approach. In this sense, several studies can contribute with this topical research, including:

- Preclinical studies (in silico, in vitro, in vivo) on analgesic and neuromodulator effects of natural products;

- Biotechnological studies demonstrating methods of improving the neuromodulator effect, stability, bioavailability and/or reduction of adverse effects of well-defined bioactive compounds or plant extracts;

- Clinical trials performed to test the efficiency of natural products to control human painful conditions;

- Systematic reviews and metanalysis about the effectiveness of well-defined bioactive compounds or plant extracts to control pain and its clinical applications.


For manuscripts dealing with plant extracts or other natural substances/compounds, the composition and the stability of the study material must be described in sufficient detail. The level of purity must be proven and included. Please refer to the Four Pillars of Best Practice in Ethnopharmacolog, a subset of which concerning general standards in natural product research are applied to all such studies in all sections of Frontiers in Pharmacology.


Keywords: pain, nociception, natural products, secondary metabolites, phytochemicals, medicinal plants


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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