Clinical Updates on Substance-P Antagonist in Pain Management

Abstract

EditorialNovel drug designing and development is the need and the decisive target of pharmaceutical industry, as the active life of a drug is not very extensive. Substance P (SP) is considered as the prototypic neuropeptide of the more than 50 known neuroactive molecules, and is also the member of a new neurotransmitter system that belongs to the family of three related peptides known as neurokinins and a member of the seven-transmembrane G-protein coupled family of receptors and is primarily associated with sensory neurons in the periphery and specific areas of the CNS [1,2]. The other two members are simply called neurokinin A and neurokinin B. Modulation of SP activity offered a radical new approach to the management of depression, anxiety, stress and is involved in several physiologic activities, including the vomiting reflex, defensive behavior, change in cardio-vascular tone, stimulation of salivary secretion, smooth muscle contraction and vasodilatation [3,4]. Substance P (SP) and its antagonist represent a radical new approach to the management of a number of diseases. SP is considered to have an impact on the smooth muscles. The SP receptor is highly expressed in areas of the brain that are implicated in these behaviors, but also in other areas such as the nucleus accumbens which mediate the motivational properties of both natural rewards and drugs [5].The treatments accessible at present for chronic pain conditions are few and their use is limited by the severe side effects of these medications. For years, researchers have been trying to elucidate the molecular mechanisms that underlie central sensitization to develop novel approaches for treating chronic pain conditions. A variety of studies led to the hypothesis that SP and its NK1 receptor are involved in nociception [3,6]. However, highly specific antagonists of NK1 are failed to show significant analgesic potential in clinical trials [7], because it is not the NK1 receptor itself, but rather the spinal cord neurons that express NK1 which are pivotal for central sensitization and chronic pain [8]. Actually, they block behavioural responses to noxious and other stressful sensory stimuli at a level detectable in animal tests but fail to provide the level of sensory blockade required to produce clinical analgesia in humans [9]. According to researchers, NK1 receptor is crucial for central sensitization and chronic pain. Study of Mantyh and colleagues, which are based largely on the observations that SP is released upon peripheral noxious stimulation and activates spinal cord nociceptive-specific neurons [10], and that when SP binds to NK1, both SP and NK1 are internalized [11].For molecular and cellular characterization, synaptic mechanisms underlying the sensitization of spinal cord NK1 expressing neurons are also studied. In that study, whole-cell patch clamp recordings were performed from dorsal horn NK1 expressing neurons in an acute spinal cord slice preparation [12]. Most spino-parabrachial neurones showed the gap-firing pattern while the bursti...

Bridging the Translational Divide in Pain Research: Biological, Psychological and Social Considerations

“…In clinical trials, NK1 receptor antagonists failed to show any analgesic efficacy in patients suffering from migraines, visceral pain, osteoarthritis and fibromyalgia (Borsook et al, 2012). The differences observed between animals and humans may not only be explained by species differences in substance P/NK1 receptor but also by the lack of understanding of how NK1 receptors function and vary across species (Hill, 2000;Khan, 2015;Navratilova and Porreca, 2019). In the case of NK1 receptors, their activation induces a redistribution to endosomes that causes sustained excitation of spinal neurons and pain transmission, which is alleviated by targeting endosomal NK1 receptors.…”