Substance P: A New Era, a New Role

C. Lindsay DeVane, PharmD.

Disclosures

Pharmacotherapy. 2001;21(9) 

In This Article

Abstract and Introduction

Abstract

Substance P has been extensively studied and is considered the prototypic neuropeptide of the more than 50 known neuroactive molecules. The understanding of substance P has evolved beyond the original concept as the pain transmitter of the dorsal horn. Animal and genetic research, recent developments of nonpeptide substance P antagonists, and important changes in the understanding of neurotransmission have each contributed to the current understanding of substance P. After 7 decades, the physiologic role of substance P is known as a modulator of nociception, involved in signaling the intensity of noxious or aversive stimuli. Genetic studies in mice and development of substance P antagonists provide more recent results that support the redefinition of the central role of substance P. Evidence suggests that this neuropeptide is an integral part of central nervous system pathways involved in psychologic stress.

Introduction

The discovery of substance P was reported in 1931, but its role then was a mystery.[1] Now, after almost 70 years of investigation, substance P is perhaps the best understood neuropeptide transmitter.[2] In the 1950s, substance P was considered to be the neurotransmitter for primary sensory afferent fibers, or the pain transmitter. This indicated that substance P was concentrated in the dorsal roots of mammalian spinal cord.[3] By the 1970s, the biochemical properties of purified substance P were elucidated: a proteinaceous substance composed of amino acids that, subsequently, could be synthetically derived. Results of numerous animal studies and in vitro experiments supported the role of substance P as integral to the nociceptive process, potentiating excitatory inputs to nociceptive neurons.[3,4]

By the mid-1980s, substance P was recognized as a member of the tachykinin family of neurotransmitters.[3] The broad term tachykinin refers to a family of neuropeptides that have a common C-terminal amino acid sequence with a varying N-terminal sequence and substance P-like activity. Of the many tachykinins found in nature, only those found in mammals are referred to as neurokinins. In addition to substance P, two other neurokinins (discovered in 1983) are known to exist: neurokinin A (NKA) and neurokinin B (NKB).[3] The significance of the varying N-terminal is thought to be related to recognition of specific neurokinin receptor sites.[3] Three categories of neurokinin receptors have been characterized, all binding substance P to some degree. Neurokinin 1 (NK1) receptors have the greatest affinity for substance P, whereas neurokinin 2 (NK2) receptors bind preferentially to NKA and neurokinin 3 (NK3) receptors bind primarily to NKB.[5,6]

The role of substance P was not fully appreciated by the end of the 1980s, even though it had been identified in the spinal cord dorsal horn.[4] Substance P was still considered to be the primary nociceptive transmitter in afferent sensory fibers,[3] released in response to noxious cutaneous stimuli and participating in conduc-tion across sensory afferent nerves (C-fibers).

The role of substance P became clearer when the site of action was closely examined at NK1 receptor sites. Localization of neuropeptide receptor systems to specific neurons is accomplished through a number of processes, including immunochemistry, receptor autoradi-ography, and in situ hybridization.[7] Substance P and NK1 are found in numerous regions in the central nervous system (CNS)[8] but are highly concentrated in the most superficial regions of the dorsal horn (substantia gelatinosa).[2,4] The dorsal horn is the first relay station of primary afferent signals where information to the brain is integrated.[2] Primary nociceptive afferent fibers terminate in the dorsal horn[2,4] and are intrinsic to processing sensory nociceptive information. As many as 40% of contacts with nociceptive fibers are with substance P-containing terminals, whereas only 2% of the contacting terminals are in contact with nonnociceptive fibers. Thus, data presented in the 1990s supported the role of substance P in processing noxious sensory information to the brain.

Recent research has shown that specific substance P pathways exist in the CNS[8] and that substance P is a neuroactive peptide that regulates the excitability of dorsal horn nociceptive neurons.[4,8,9] Substance P and NK1 are present in small-group neurons throughout the neuroaxis that are involved in the integration of pain, stress, and anxiety. In addition to the spinal cord, substance P is present in the limbic system of the CNS, including the hypothalamus and the amygdala -- areas associated with emotional behavior.[6] Neurokinin 1 is highly expressed in the hypothalamus, the pituitary, and the amygdala -- brain regions that are critical for the regulation of affective behavior and neurochemical responses to stress.[8] Also associated with the amygdala are neural pathways that respond to stressors -- noxious or aversive stimulation.[8]

Substance P also 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 vasodilation.[10,11] At least one of these activities (i.e., changing cardiovascular tone) changes along with behavior as part of the defense response to threatening stimuli or trauma in animals.[10,12] Stimulation of the amygdala in response to fear or anxiety triggers such autonomic responses and adaptive behaviors. In addition, such stimulation of the amygdala is associated with endogenous substance P release.[10]

Important developments in the understanding of substance P and its role in physiologic processes, including nociceptive (pain) responses and neurogenic inflammation, are reviewed. Recent studies with nonpeptide substance P antagonists and genetic mutations in mice have helped to refine the understanding of the role of substance P in pain and in response to stress. The results of a clinical trial that implicate the substance P system in depression and anxiety are reviewed and suggest that substance P antagonists should be developed as a new class of drugs and as an effective alternative or adjunct to current pharmacotherapy for these disorders.

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