Pain is a prevalent complex medical problem, characterized by physically debilitating and mentally destabilizing conditions. Current pain therapeutics mainly include non-steroidal anti-inflammatory drugs and narcotics (opioids), but they exhibit limitations in efficacy, unwanted side effects and the problem of drug abuse. To overcome these issues, the discovery of different molecular players within pain pathways could lead to new opportunities for therapeutic intervention. Among other strategies, peptides could be powerful pharmaceutical agents for effective opioid-free medications for pain treatment. This review is a compendium of representative non-opioid analgesic peptides acting directly or indirectly at different ion channels and receptors distributed in nociceptive pathways. They include peptides targeting Ca 2+, Na+ and K+ voltage-gated ion channels, the neuronal nicotinic receptors (nAChR), transient receptor potential channels (TRP), and different non-opioid G-protein coupled receptors (GPCRs), like the calcitonin gen-related peptide (CGRP), cannabinoid, bradykinin and neurotensin receptors, among others. Peptides engineered from protein-protein interactions among pain-related receptors and regulatory proteins also led to new therapeutic approaches for pain management. Following some successful examples, already in the clinics or under clinical trials, the improved understanding of pain mechanisms, and the advances in peptide permeation and/or delivery, could afford new analgesic peptides in the near future.
Pain is defined by the International Association for the study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. Pain can be classified attending to its duration as acute (<6 months) or chronic (>6 months), and to its underlying cause as inflammatory due to tissue damage or neuropathic caused by damage to the nervous system by surgery, fractures, cancer, diabetes, infections, and chemotherapy [1]. Pain plays a protective role from injury. However, chronic pain is a useless sensation, which interferes with sleep, work, and quality of life, becoming a disease by itself.
Pain involves an extremely complex and interrelated series of signaling and modulatory pathways of the nervous system, starting at the periphery, and transmitted via the dorsal horn to brain structures [1]. Currently, pain management remains a complex and difficult task, with all mediators involved in pain signaling being considered potential targets for therapeutic intervention [2]. Current analgesic drugs, mainly targeting the endogenous opioid system or the enzymatic cascade related to inflammatory processes (NSAIDs), neither provide universal pain relief nor are exempt of harmful effects. However, in this new century only four new chemical entities (NCE) entered the market for pain treatment [3]. Hence, the discovery of specific and effective treatments needs of constant research to advance in deciphering pain mechanisms, from validating translational targets to developing innovative therapies.
Since the discovery of opioid peptides in the 1970s, a huge effort has been devoted to develop new analgesic peptides devoid of the side-effects of morphine and other narcotics, namely tolerance and dependence. However, to the best of our knowledge, none of these efforts has resulted in novel analgesics for clinical use, although some compounds are still under clinical studies [4,5].
Recent advances in the understanding of the precise contributions of different molecular players to pain sensation and transmission are opening new avenues for therapeutic intervention in this field. There are two factors that have contributed in a decisive way in recent years: a) the progressive unraveling of ion-channel-mediated circuits in pain sensation and induction [6,7], and b) the discovery of a plethora of peptide-derived venom toxins from animal sources able to modulate different pain targets [[8], [9], [10], [11]]. In fact, the combination of these two factors resulted in the first peptide derivative launched for pain relief, namely Ziconotide (Prialt®) [5], as discussed in more detail below.
Despite the well-known limitations, such as instability, short duration of action and difficulties to cross cell membranes, the use of peptides as therapeutics is constantly increasing, with about 60 marketed peptides and over 150 under clinical development [12]. Peptides are always well positioned in medicinal chemistry programs, especially to tackle targets difficult to control by small-molecules or biologic therapeutics, due to the potency and specificity for their targets, and the effective metabolism to non-toxic metabolites. The field of pain management is not an exception, with different peptides used as pharmacological tools to understand nociceptive transmission and even to provide potential new treatments [[13], [14], [15]].
Since opioid peptides has extensively been reviewed in recent years [4,[16], [17], [18], [19], [20]], this compendium will cover the most representative examples of peptides with antinociceptive/analgesic properties through the modulation of non-opioid systems (2000–2018). Without the aim of being exhaustive, this review focuses on peptides able to modulate different types of ion channels (Ca 2+, Na+, K+, nAChR, TRPs, etc.), and non-opioid GPCRs, including the CGRP system, cannabinoid, bradykinin and neurotensin receptors, among others. Also the interference within relevant protein-protein interactions (PPI) in pain pathways is addressed here as an innovative approach for pain relief.
It is well established that voltage-gated Ca 2+ channels (VGCCs) are mediators of pain signals in primary afferent neurons, especially N and T-types [21,22]. N-type Ca 2+ channels (Ca v 2.2) are highly expressed in neurons, co-localized with pain-inducing neurotransmitters (substance P, CGRP and glutamate), and are unregulated in spinal dorsal horn during pain states. T-type channels are located on sensory pathways, with the Ca v 3.2 as the most prominent isoform in nociception. Therefore, blocking
During the past decades, the research around G-protein coupled receptors (GPCRs) responsible of pain transmission and control has been centered in studies on the opioid system, and interrelated GPCRs, like neurokinin, opioid-like, orexin and NPFF/QRFP receptors. None of these systems are contemplated here because it is difficult to cover the vast number of peptides in a single review, and most of them are covered by some recent reviews [20,[131], [132], [133]]. The role of other GPCRs, like the
Stable or dynamic protein complexes, either as responsible of the organization of active sites in oligomeric enzymes, receptors or ion-channels, or by participating in regulatory processes, are key signaling players. As such, protein-protein interactions (PPI) networks represent an important group of targets for therapeutic intervention [[204], [205], [206]]. Cumulative evidence unveiled direct or indirect interactions among pain-related receptors and their regulatory/associated proteins [207],
Neurotrophins such as NGF regulate the development of the nervous system, produce pain and are upregulated in inflammatory pain. In contrast, the activity of glial-derived neurotrophic factor (GDNF) and artemin serve to attenuate neuropathic pain [227]. Therefore, blockade of neurotrophins could result in alternative analgesic treatments. In fact, different antibodies and fragments, having binding specificity for NGF, reached clinical trials for the efficacious treatment of various chronic pain
Pain is a colossal clinical problem both by the number of patients affected worldwide and by the huge health care costs. Pain affects critically the quality of life of patients and their families. This is additionally aggravated by the lack of response of several pain types to existing drug pain killers, as well as by the adverse effects (i.e., tolerance and dependence with opioids) that limit their use for chronic conditions. The enormous advances in recent years about the mechanism of pain
This work was supported by the Spanish Ministry of Economy and Competitiveness [SAF 2015-66275-C2-R]; and Consejo Superior de Investigaciones Científicas, Spain (201580E073, 201880E109).
