Substance P: A New Era, a New Role

C. Lindsay DeVane, PharmD.

Pharmacotherapy. 2001;21(9) 

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.

Defining a Physiologic Role

Pain and Neuronal Transmission

Intense peripheral stimulation may induce release of substance P into the dorsal horn, causing central hyperexcitability and an increased sensitivity to pain.[13] Although high concentrations of substance P are present in the dorsal horn, it is not the primary afferent transmitter, contrary to early proposals. Electrophysiologic evidence shows that iontophoretic application of substance P to dorsal horn neurons causes a delayed, slow, and prolonged excitation.[2,4] The slow response to substance P was the first evidence that excluded it as a primary afferent transmitter. Instead, researchers suggested that substance P modulated or regulated synaptic transmission in the dorsal horn, based on the afterdischarge response that occurred only with sustained noxious stimulation.[2] Substance P appears to have a role in potentiating both excitatory and inhibitory inputs to spinal nociceptive neurons, in effect sensitizing the neurons to any synaptic input.[2]

More than one mechanism of action may account for the slow, prolonged effect of substance P at the neuronal level. Researchers have postulated that several cellular systems integrate the effects of substance P.[2] With prolonged noxious stimulation, substance P and excitatory amino acids (glutamate or aspartate) are released from the primary afferent terminal, binding to the neuronal cell membrane NK1 and N-methyl-D-aspartate (NMDA) receptors, respectively (Figure 1). After binding, cell excitation occurs with calcium ion influx into neuronal cells by means of membrane-dependent events. Nitric oxide is formed intracellularly by a calcium-dependent nitric oxide synthase reaction. The fact that an inhibitor of this reaction, N[G]-nitro-L-arginine methyl ester (L-NAME), causes attenuation of dorsal horn neuron responses to iontophoretic application of substance P suggests that nitric oxide plays a role in the substance P pathway.[2]

Figure 1.

 

Steps involved in the activation of L-arginine-nitric oxide pathway after the release of substance P and excitatory amino acids (EAA) from the primary afferent terminals. Evidence suggests that nitric oxide formed in the stimulated neuron may not activate the formation of cyclic guanosine 3',5'-monophosphate (cGMP) in the same neuron because the elevated intracellular calcium in the neuron may inhibit the activation of guanylate cyclase. Nitric oxide, an easily diffusible gas, may diffuse into the neighboring neurons and activate guanylate cyclase in those target neurons to form cGMP from guanosine triphosphate. NMDA = N-methyl-D-aspartate receptor; NOS = nitric oxide synthase; GC = soluble guanylate cyclase; + = activation; - = inhibition. (From reference 2 with permission.)

Substance P and Neurogenic Inflammation

The development of intrapulmonary immune complexes results in inflammation, characterized by microvascular permeability and polymorphonuclear neutrophil influx with resultant localized edema.[14] Neurogenic inflammation also involves the release of substance P from sensory nerve endings in response to pain or infection. When the irritant capsaicin was applied to skin, edema occurred as a result of sensory neuropeptide release, including substance P.[1] The effect of substance P in edema formation could be blocked by substance P antagonists that previously were characterized as blockers of neurogenic inflammation.[4] Neurogenic inflammation was also examined in mice with immune complex-mediated acute lung injury and associated microvascular permeability. Vascular permeability is strongly mediated by substance P, and substance P-containing C-fibers are part of the mucosal epithelium lining of the lungs.[14] When mice deficient in the receptors for both substance P and complement factor C5a (intrinsic to the inflammatory response) were studied for protection of the lung from immune-complex injury, either deficiency alone provided protection.[14] This suggested that both substance P and C5a bound to their G protein-coupled receptors were essential for immune-complex inflammatory lung injury. Substance P is critical to the inflammatory cascade in amplifying immune-complex injury to the lung by acting at the microvasculature of the airway mucosa. The results of these studies suggest that neuropeptide regulation of neurohumoral responses is at least partially mediated by substance P.

Neuropeptide Colocalization and Substance P as a Neurogenic Regulator

The classic view of neurotransmission stated that presynaptic neurons secreted only a single substance that resulted in either the activation or the inhibition of the postsynaptic receptor neuron. However, it is now generally believed that many, if not most, contain multiple transmitter molecules.[7] For example, substance P coexists with other transmitter molecules in the afferent dorsal horn nerve terminals, including vasoactive intestinal peptide, galanin, neurotensin, and cholecystokinin, among others.[2] Opioids, which inhibit the postsynaptic responses by dorsal horn neurons, are also present with substance P in the dorsal horn. However, substance P is not an opioid.[2,13] Similar to substance P, NKA is localized in the dorsal horn and provokes a slow, prolonged response by nociceptive neurons; however, unlike substance P, NKA also excites nonnociceptive neurons.[2,4,15] The functional significance of colocalization of several neuropeptides or neuropeptides with other chemicals in one terminal is not fully understood.[2]

Even though colocalization does not confirm cotransmission, substance P works in concert with several hormones and transmitter or signaling molecules. For example, in rats the number of NK1 receptors on lactotrophs and gonadotrophs in the anterior pituitary varies throughout the estrous cycle, as do levels of estradiol.[5] The midcycle 17 b-estradiol surge is responsible for synchronizing the interactive mechanisms of the hypothalamopituitary complex that lead to the midcycle luteinizing hormone (LH) surge.[5] In female rats, substance P inhibits the amplitude of the midcycle LH surge.[5,16] This is consistent with data that suggest there is an increase in substance P secretion from the hypothalamus during the descending phase of the LH surge of the estrous cycle. A study in ovariectomized monkeys showed that use of an NK1 receptor antagonist resulted in enhanced LH and follicle-stimulating hormone (FSH) concentrations during the descending phase of the LH and FSH surge.[5] Substance P regulation of the LH surge appears in monkeys and rats, implicating substance P in hormonal responses of the hypothalamopituitary axis.[5]

Substance P and angiotensin II are colocalized in the dorsal medulla oblongata of both the dog and rat. Here, angiotensin II mediates the action of substance P.[17] Substance P causes endothelium-dependent vasodilation mediated through the NK1 receptor on endothelial cells.[11] Decreased plasma concentrations of endogenous substance P were found in stroke-prone, spontaneously hypertensive rats and in humans with essential hypertension.[11] This suggests that diminished substance P concentrations can result in a loss of counterregulatory vasodilation activity, thereby partially explaining essential hypertension.[11] Low doses of both substance P and angiotensin II injected into the nucleus tractus solitarii cause hypotension and bradycardia, which can be blocked by administration of a substance P antagonists.[17]

Cotransmission of serotonin and substance P probably occurs in the neuronal pathways in which they are both present.[7] Indirect evidence from studies of human brain tissue suggests that substance P and serotonin are coexpressed in a proportion of neurons of the dorsal raphe,[10] an area where many serotonergic neurons originate. Conversely, coexpression of substance P and serotonin does not occur in the raphe of rat brain, implying a physiologic species difference. The result shows that conclusions about the interactions between serotonin and substance P are complicated when interspecies functional comparisons are made. Therefore, animal models should be carefully characterized relative to humans before conclusions about human physiology are made. Substance P antagonists can be divided into two groups based on species-dependent NK1 receptor affinity. Group one includes compounds with high affinity for NK1 receptors in humans and guinea pigs, and the other group of compounds have a high affinity for rat or mouse receptors. The guinea pig model has been especially helpful in understanding the actions of substance P antagonists, particularly in preclinical studies. Studies in guinea pigs have shown that infusion of a substance P agonist caused long-lasting audible vocalizations,[8] which could be stimulated naturally in guinea pig pups separated from their mothers and littermates. Substance P antagonists that penetrate the CNS and have a high affinity for NK1 receptors (L-760,735 and L-733,060) completely halted separation-induced vocalizations in guinea pig pups, showing that substance P antagonism successfully inhibits the behavioral response to a stressful stimulus. Results in this novel animal model suggest that psychologic stress causes substance P release in the amygdala.[10]

Contribution of Substance P Antagonists

The initial studies with substance P antagonists yielded conflicting results because of an incomplete understanding of substance P actions and the inability to produce a stable, selective substance P antagonist that could enter the CNS.[1,3] In the last decade, nonpeptide substance P antagonists with good CNS penetration have been developed.[4] These new antagonists have provided important new tools for investigating substance P participation in nociceptive transmission and activity in the CNS.

Substance P antagonists originally were studied by measuring spinal nociceptive reflexes (tail flick latency and hind paw favoring) in rats after noxious mechanical (tail pinch), thermal (tail bath), or chemical (formalin injection at hind paw) stimulation. In one study, a substance P antagonist was examined for its effects on the substance P-induced latency in spinal reflex tail flick after noxious stimulation. After subcutaneous administration of CP-96,345 (a prototypic, nonpeptide NK1 receptor antagonist), intrathecal substance P did not induce a latency in tail flick, indicating that this antagonist interacted with spinal NK1 receptors and blocked substance P action.[18] In another study, CP-96,345 attenuated the second, prolonged phase of hind paw favoring after chemical stimulation (formalin) but had no effect on the immediate, short response.[18,19] Also, CP-96,345 and CP-99,994 altered dorsal horn neuron responses from noxious cutaneous stimulation (thermal or mechanical).[2,4] These substance P antagonists consistently inhibited the late afterdischarge phase of the neuronal response but did not affect baseline firing or initial components of the response.[2,4] In contrast, nonnoxious stimuli produced a rapid response from dorsal horn neurons, and substance P antagonists did not block this response.[2] Overall, substance P antagonists did not alter the acute pain threshold after a brief noxious stimulus; however, after more prolonged noxious stimulation, the responses were modified.[4] The substance P antagonist data are compelling and show that the primary substance P receptor, NK1, is not involved in the fast component of the nociceptive response. Therefore, substance P is not the primary pain transmitter.[2]

These studies of the involvement of substance P in the prolonged response to pain are supported by recent research indicating an important role for substance P in stress responses. For example, stimulation of neuronal substance P pathways by central injection of a substance P agonist produced a range of defensive behavioral and cardiovascular changes in animals, a response consistent with reactions to stressful stimuli.[12,20-22] Also, studies have shown that the content of substance P changes in discrete brain regions after stressful stimuli, and the authors describe release of substance P in the basolateral amygdala after neonatal separation stress in guinea pigs.[8] Therefore, results from many studies in animals have shown that endogenous substance P release occurs as part of the response to stress.[10,20-22]

To further investigate the stress response, several NK1 receptor antagonists have been used to selectively inhibit the substance P activity involved in behavior in response to stress. In rats, the substance P antagonist GR-205171 inhibited an increase in the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex resulting from 20 minutes of restraint stress.[23] Another study in rats showed that neuronal firing in the locus ceruleus was increased by the central administration of substance P and that actuation of the ascending noradrenergic projection of the locus ceruleus resulting from stress induced by immobilization was inhibited by substance P antagonists RP-67580 and L-760,735.[24] Thus, substance P appears involved in stress-induced activation of catecholamine systems.[10]

To define the pathophysiology and investigate potential treatments of stress, potent nontoxic substance P antagonists that could penetrate the CNS were needed. However, a number of the original substance P antagonists used in earlier studies could not penetrate the CNS, a considerable obstacle to further research efforts. Since then, newer substance P antagonists have been more successful. The results of a study in ferrets, which showed that focal injection of newer NK1 antagonists into the nucleus tractus solitarii inhibited cisplatin-induced emesis, confirmed a CNS site of action.[25] Subsequently, clinical trials with three different orally administered substance P antagonists (CJ-11974, CP-122721, and MK-869) demonstrated that they are extremely effective in preventing delayed emesis after cisplatin chemotherapy, indicating an ability to cross the blood-brain barrier.[26-28] After chemotherapy, serotonin may be released from enterochromaffin cells of the digestive tract, which then activates visceral afferent neurons. These peripheral neurons terminate in the chemoreceptive trigger zone (area postrema) of the hypothalamus, which is the high-density location of the substance P-NK1 peptide system.[29] Thus, substance P is critical in the response to prolonged pain, including the emotional pain of stress and anxiety, and in chemotherapy-induced emesis. Research is ongoing in the role of substance P and possible therapeutic applications of substance P antagonists in other disorders such as migraine and asthma.

Defining a New Role

Studies to further characterize the role of substance P as a modulator of pain information into the CNS were performed in mice with genetically altered substance P systems. Knockout mice, with the NK1 receptor gene disrupted, completely lacked the windup phenomenon.[13] This phenomenon refers to the increased response of C-fibers after repetitive activation of the C-fiber and in this study was documented by electromyographic activity recorded in the anesthetized mouse while mechanical or electrical stimulation was applied to the hind paw. The normal response reflects sensitization of CNS mechanisms (C-fibers) by intense noxious stimulation.[13] These knockout mice experiments showed that NK1 receptors are necessary to mediate substance P actions in the nociceptive windup response, an index of CNS sensitization. Therefore, the substance P-NK1 receptor system is involved in CNS sensitization.

A second study was performed in mice with a disrupted PPT-A gene, which encodes substance P and NKA. The lack of substance P and NKA did not alter responses to mildly painful stimuli.[9] However, responses to moderate and intense pain were significantly reduced in the mutant mice. A "window" seemed to be present for the importance of substance P and NKA, as an even greater intensity of the pain stimulus resulted in a similar response in the knockout mice compared with that in wild-type mice with PPT-A genes.[1] The knockout mice also showed impaired neurogenic inflammatory responses but responded normally to inflammatory stimuli without a neurogenic component.[9,14] Therefore, the genetic expression of the PPT-A gene and subsequent synthesis of substance P and NKA neuropeptides are needed during the neurogenic inflammatory response in mice.[9,13,14]

Role of Stress in Depression

As animal models have shown, substance P is released as a part of the response to stress, and environmental stress is thought to contribute substantially to changes in the CNS that predispose individuals to depression. Several other mediators are involved.[30-32] Much of what is understood about the neurobiology of depression results from studies with anti-depressant drugs.[31] Pharmacologic interventions that affect biogenic amines are considered to be important in the initiation and maintenance of antidepressant activity. However, these interactions are only the first step in a complex sequence of neurobiologic events that are involved in antidepressant effects. Chronic antidepressant effects on biogenic amines may result in protecting neurons from further damage or possibly reversing the atrophy and damage that has occurred, potentially as a result of stress.[32] Chronic administration of antidepressants upregulates the cyclic adenosine 3¢,5¢-monophosphate (cAMP) second messenger system and increases expression of brain-derived neurotropic factor.[30,31] Brain-derived neurotropic factor is a member of a family of neurotropic factors that are important in maintaining survival and function of neurons and are found in high levels in the hippocampus and cerebral cortex of adults.[30,31] The expression of brain-derived neurotropic factor is downregulated during stress.[31]

If the hypothalamic-pituitary-adrenal axis is excessively stimulated by adverse events, corticotropin-releasing factor secretion is increased and consequently glucocorticoid concentrations increase.[31] Studies show neurons of the hippocampus are damaged by long-term exposure to stress or activation of the hypothalamic-pituitary-adrenal axis and resultant increased concentrations of glucocorticoids. This is demonstrated by a reduction of hippocampal volume in these patients.[30-32] Some studies have shown that depressed patients also have reduced hippocampal volume.

Increased glutamate release and the excitotoxic effects of calcium ions (Ca2+) have been implicated in contributing to the neuronal damage mediated by glucocorticoids.[31,32] Glutamate increases intracellular levels of Ca2+, which has been linked to the excitotoxic effects of repeated seizures and ischemia. Several questions remain unanswered regarding the roles of stress and elevated glucocorticoid level, with its excitotoxic effects, in hippocampal neuronal damage and depression, but the potential exists for several novel therapeutic approaches to depression.

Clinical Implications of the Substance P Antagonist MK-869

Supporting data for the role of substance P antagonists in the treatment of depression and anxiety can be found in studies demonstrating that these agents block certain stress-induced behaviors in animal models.[8] Clinically available antidepressants produced a similar positive effect, whereas compounds with a weak affinity for NK1 receptors failed to inhibit vocalizations. The guinea pig model was instrumental in supporting the clinical development of MK-869, a nonpeptide substance P antagonist with a high affinity for the guinea pig and gerbil NK1 receptors and a high selectivity for human substance P receptors.[8]

Preclinical trial results suggested that MK-869 produced both antidepressant and anxiolytic effects. On the basis of results from the guinea pig vocalization model and the current understanding of substance P in neuronal pathways, MK-869 was studied in patients with both depression and anxiety. One study reported results from a multicenter, double-blind, 6-week trial of outpatients with major depressive disorder and moderate anxiety who were randomly assigned to paroxetine 20 mg/day (72 patient), MK-869 300 mg/day (71 patients), or placebo (70 patients).[8] Patients studied were experiencing a depressive episode of at least 4 weeks' but less than 2 years' duration and had at study initiation a score of 22 or higher (moderately depressed) on the Hamilton Rating Scale (HAM) for Depression (17-item, HAM-D17). A score of 15 or higher (moderately high anxiety) on the HAM for Anxiety (14-item, HAM-A) and a score of higher than 4 (moderately ill) on the Clinical Global Impressions (CGI) scale were also required for study participation. Patients using other psychotropic drugs underwent a 7-day (4 weeks for fluoxetine and 14 days for monoamine oxidase inhibitors) washout period before beginning the study. Patients were allowed to use chloral hydrate (500-1000 mg/day) sparingly for insomnia, but not within 24 hours of a visit. No other psychotropic drugs were permitted.

The 300-mg dose of MK-869 was predicted to achieve greater than 90% blockade of central substance P receptors, and this dose was well tolerated during the study. Primary efficacy was evaluated by using the HAM-D21 total score. Secondary end points included the HAM-A total score and the CGI severity scale (CGI-S). The mean change from baseline to week 6 for the HAM-D21 differed by 4.3 points between the placebo-treated group and the group receiving MK-869 (p=0.003) (Figure 2). The 4.3-point difference with MK-869 was comparable to a 3.6-point difference from placebo after 6 weeks of paroxetine (p=0.01). The change in HAM-D21 total scores with MK-869 was observed at all investigative centers. A complete response (HAM-D17 < 10) at the last rating was achieved in 43% of patients receiving MK-869, in 33% of patients receiving paroxetine, and in 17% of patients receiving placebo. Secondary end points showed positive trends, and a gradually increasing anxiolytic effect occurred and persisted through the 6-week study period with both MK-869 (p=0.002) and paroxetine (not significant). Improvement of depression is known to decrease symptoms of anxiety and could explain the positive effect of MK-869 on HAM-A scores, although this effect could be predicted based on animal and neurochemical models. As a result of the findings in this study, investigation of the anxiolytic effect of substance P antagonists in nondepressed patients seems warranted.

Figure 2.

 

Effect of administration of MK-869 300 mg/day or paroxetine 20 mg/day on depression, measured as the mean change from baseline (on the Hamilton Rating Scale for Depression [HAM-D] 21-point scale) in a 6-week clinical, placebo-controlled trial of 213 outpatients, 198 of whom completed the study. MK-869 (black circle, 66 patients) and paroxetine (black triangle, 68 patients) are compared with placebo (white square, 64 patients). Error bars show 95% confidence intervals. (From reference 8 with permission.)

Mild and transient adverse effects were reported with MK-869. Headache (32%), somnolence (20%), nausea (18%), and asthenia or fatigue (14%) were the most common. None of the adverse events reported for MK-869 had a frequency significantly greater than placebo. Only the frequency of sexual dysfunction had a significant difference (p<0.05) between the paroxetine group and the MK-869 and placebo groups. This included total sexual dysfunction (paroxetine 26%, MK-869 3%, placebo 4%; p<0.05 paroxetine > placebo, p<0.05 MK-869 < paroxetine), general sexual dysfunction (paroxetine 8%, MK-869 0%, placebo 0%; p<0.05 paroxetine > placebo, p<0.05 MK-869 < paroxetine) and ejaculation disorders (paroxetine 20%, MK-869 3%, placebo 7%; p<0.05 MK-869 < paroxetine). The percentage of patients discontinuing therapy because of adverse effects was greater with paroxetine (19%) than with MK-869 (9%) or placebo (9%). Nausea was the primary adverse effect causing discontinuation in the paroxetine group (29%, p<0.05 compared with placebo), but for MK-869 or placebo, no specific adverse effect was the primary cause for discontinuation.

The initial findings reported in that study[8] encouraged further clinical development of MK-869. Recently, several hundred depressed outpatients were given MK-869, fluoxetine, or placebo in a dose-finding study.[10] In this study, fluoxetine, the known comparator, was only about as effective as placebo, an uninformative outcome. This type of result is seen in approximately 50% of drug trials involving antidepressants.[10] There are indications that poorly controlled patient selection at some centers could have contributed to the less than promising results reported in this study. However, these results may have contributed to the manufacturer's decision to suspend further development activities of MK-869 as an antidepressant, but other compelling findings have stimulated the research seeking the development of more effective compounds.[33]

Since MK-869 caused improved depressive and anxious symptoms and had a benign adverse-event profile, the potential to use substance P antagonists for other mental disorders was provocative. Notably, substance P is thought to modulate the activity of the mesolimbic dopamine system, a major site for antipsychotic drug action; however, in an exploratory, controlled trial, MK-869 in schizophrenic inpatients lacked efficacy in acute psychosis.[10] Continued clinical research in patients with mesolimbic diseases is needed to further define the promising role of substance P antagonists in restoring physiologic and psychologic balance.

A number of NK1 subtype selective antagonists, both peptide and nonpeptide, are under investigation for different indications, including depression, chemotherapy-induced emesis, migraine, and asthma. In addition, there are many substance P antagonists that are being used as research tools and are not targeted for clinical development ( ).[10,12,27,34-38]

Table 1.  Neurokinin-1 Subtype Selective Antagonists (substance P antagonists) under Development or in Use in Clinical Studies

NK1 Receptor
Antagonist
Indication
CGP-60829 Depression
CJ-11974 Chemotherapy-induced emesis
FK-888 Chronic bronchitis
GR-205171 Chemotherapy- and radiation therapy-induced emesis; migraine
L-754,030 Chemotherapy-induced emesis
MK-869 Chemotherapy-induced emesis
NKP-608 Depression
SR-140333 Asthma and inflammation

Conclusion

Preliminary clinical studies and original research on substance P have contributed to the understanding of substance P as a neuroactive peptide. After 7 decades of research, at least part of the physiologic role of substance P is now understood to be a modulator of nociception, involved in signaling the intensity of noxious or aversive stimuli. The role of substance P as a regulator of pain information is supported by the identification of NK1 receptors in the CNS, the peripheral nervous system, and the anterior pituitary.[5] The development of nonpeptide substance P antagonists, assessments from experimental and genetic techniques, and important shifts in theories of pain and neurotransmission have advanced our understanding of the prototypic neuropeptide substance P beyond the concept of the pain transmitter. This progress also contributed to a better understanding of other neuropeptides.

The presence of NK1 receptors in the limbic system and hypothalamus suggests a role for substance P in emotional behavior.[13] This new concept is supported by animal studies. Mice devoid of NK1 receptors were considerably less aggressive in the resident-intruder test,[39] and cats administered NK1 antagonists lost their defensive rage response that normally occurs after medial hypothalamic stimulation.[40] These and other studies with substance P antagonists confirm that substance P is an integral part of the neuronal pathways involved in responses to stressful stimuli, including pain, injury, invasion of territory, or psychologic stress.[13] This understanding has stimulated the search for clinical applications of substance P antagonists. In particular, the promising results of MK-869 in patients with mixed anxiety-depression provide strong incentive for continued development of substance P antagonists to treat diseases associated with emotional response and with the interpretation of sensory input to the brain.

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