Clinical Applications of Substance P (Neurokinin-1 Receptor) Antagonist in Canine Medicine

1. Context

Substance P is the first neuropeptide discovered in mammals in 1931( 1 ). It binds to Neurokinin-1 (NK-1) receptors found in the emetic center of the CNS and induces emesis as a result ( 2 ). Therefore, selective substance P antagonists can act as potent broad-spectrum antiemetics in dogs and cats against various emetic stimuli ( 2 ). The NK-1 receptor antagonists are widely used in chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting ( 3 , 4 ). The brain stem regions (i.e., area postrema and nucleus solitaries) are concerned with vomiting reflexes ( 5 ).

Recently developed NK1 receptor antagonists, such as aprepitant can cross the blood-brain barrier, which makes them useful in a wide range of CNS disorders ( 6 ). Furthermore, NK1 antagonists play a role in tumor treatment ( 7 ). Apart from this, substance P and its derivatives are also used in targeted radionucleotide diagnosis of tumors (8). However, the application of substance P-derived medical products is limited since endogenous substance P is a potent vasodilator mediated by nitric oxide ( 9 ).

It should be noted that NK11 is present in both the central nervous system and peripheral tissues, where it plays a role in the transmission of pain, the transition of inflammatory response at peripheral sites (e.g., gastrointestinal and respiratory tract), stress, and anxiety ( 10 ). As a selective NK-1 receptor antagonist, maropitant is approved to prevent and treat vomiting in dogs. It is also available in both injectable and tablet formulations and can be used for managing motion sickness ( 10 ).

Maropitant is a strong antiemetic and has also been used as pre-anesthetic due to its antiemetic property and capacity to alleviate visceral pain originating from abdominal and thoracic organs ( 11 ). It also helps canine patients to resume food intake more quickly in the postoperative phase ( 12 ). Vasodilation and increase in vasculature permeability occur upon release of the neuropeptides from endings of the sensory nerves. These functions are blocked by the NK1 receptor antagonists when administered intra-arterially. Transdermal application of iontophoretic in animals reduces pulpal pain by blocking substance P induced pulpal blood flow in dental treatments ( 13 ).

The drug rolapitant is a highly potent, sensitive, orally active, and long-acting NK1 receptor antagonist with a half-life of 180 h ( 14 ). Another drug netupitant demonstrated synergistic effects of palonosetron through the inhibition of substance P response ( 13 ). The longer half-life overcomes the problem of repeated administration in cases of acute and delayed emesis ( 15 ). The pool of options thus helps choose the optimal regimen that best suits the animal in various aspects (e.g., cost, tolerability, availability, and safety).

2. Evidence Acquisition

This review aimed to discuss and analyze the therapeutic potential of substance P (Neurokinin-1 receptor) antagonist with a particular focus on the drug maropitant in canine medicine. A systematic literature review was performed to identify the related literature in the past 20 years (2001-2021) using such databases as ScienceDirect, PubMed, Scopus, and Google Scholar. The search keywords included “substance P”, “Neurokinin-1 receptor antagonist”, “maropitant”, “antiemetic”, “uremic gastritis”, and “canine medicine”. The inclusion criteria used for selecting the related literature included the availability of information on substance P (NK-1) receptor antagonists, properties, side effects, and therapeutic potential focusing on canine medicine. The results did not include articles written in languages other than English.

3. Results

The initial search identified 173 articles, and the relevant, critical, and most recent studies were given preference. Based on the specific inclusion and exclusion criteria, 41 articles were selected for further analysis. The obtained data were used for developing this review.

3.1. Substance P (Neurokinin-1 Receptor) Antagonist

Substance P is a neuropeptide (11 amino acids) belonging to the tachykinin family ( 16 ). Substance P (NK-1) receptor antagonist inhibits the binding of substance P to NK-1 receptors (Figure 1) ( 2 ). Preliminary studies have confirmed the role of substance P and NK-1 receptors in central pain processing, intestinal smooth muscle contraction, vasodilation, and neurogenic inflammation ( 10 , 16 ). In addition, substance P is involved in the physiological functions of the gastrointestinal tract, such as fluid and electrolyte secretion, motility, and immunoinflammatory response regulation ( 17 ).

Figure 1. Schematic presentation of Neurokinin-1 (NK-1) receptor (long isoform-full length with 407 amino acids) containing an extracellular N-terminus, three extracellular loops (E1, E2, and E3), four intracellular loops (C1, C2, C3, and C4), and seven transmembrane domains. Reproduced by Garcia-Recio and Gascón (2015) (5) under Creative Commons Attribution License (CC-BY).

Maropitant is the first NK-1 receptor antagonist used in veterinary practice ( 2 , 18 ). It is also one of the most effective veterinary antiemetic drugs that are currently in use. They work well against peripheral and central emetogens ( 19 , 20 ). On the contrary, other antiemetics prevented vomiting caused by either peripheral (ondansetron) or central (chlorpromazine and metoclopramide) stimulation, not both ( 20 ). Other examples of NK-1 receptor inhibitor include aprepitant, casopitant, fosaprepitant netupitant, and rolapitant ( 21 ). Higher expression of NK-1 receptors in muscle and mucosal immune cells of inflamed tissues could be considered a rationale for using NK-1 receptor antagonist drugs for treating intestinal inflammation ( 17 ).

3.2. Broad-Spectrum Antiemetic Drug

Emesis is one of the most common signs of gastrointestinal dysfunction in small animals ( 19 ). Vomiting can cause severe dehydration, reflux esophagitis, weight loss, and aspiration pneumonia if not controlled at the early stages ( 2 ). An antiemetic is indicated when vomiting is severe and/or persistent ( 2 , 22 ). They can help reduce the frequency of vomiting and prevent further aggravation of acid-base and electrolyte imbalance ( 2 ). Several pathways constitute multiple inputs, and the involvement of co-transmitters contributes to different arms of the vomiting reflex. Therefore, antiemetic drugs have to be selected based on the triggered pathway of the vomiting reflex ( 19 ). An ideal antiemetic drug will prevent both central and peripheral stimuli that trigger the vomiting center ( 19 ).

Maropitant has already demonstrated therapeutic efficacy in dogs for managing acute vomiting associated with pancreatitis, gastritis, and parvoviral enteritis ( 23 - 25 ). Promising results were obtained after the administration of one or two doses of maropitant, indicating very high efficacy ( 24 ). In addition, a single daily dose protocol of maropitant was found to be more effective than metoclopramide administered twice or thrice daily for the treatment of emesis associated with various etiologies in dogs ( 26 ). Maropitant can also be used to prevent and treat chemotherapy-induced emesis in dogs ( 27 ). These also delay chemotherapy-induced signs of nausea and adverse gastrointestinal effects in dogs (27, 28). Maropitant is combined with loperamide to prevent paclitaxel-induced adverse gastrointestinal effects ( 28 ). It has shown similar efficacy to ondansetron for controlling the clinical signs (e.g., vomiting) associated with parvoviral enteritis in dogs ( 25 ).

The standard antiemetic dose of maropitant for dogs is 1 mg/kg q 24h, indicating a 24-h duration of the effects ( 19 ). It is administered subcutaneously and has an elimination half-life of 4 to 8 h in dogs ( 2 ). However, a higher dose is recommended (8 mg/kg PO q24h) for managing motion sickness in dogs. In addition, the animal has to fast for 1 h before the oral administration of maropitant at this dosage ( 2 , 19 ). The absolute bioavailability of maropitant is low after oral administration (23.7% at 2 mg/kg) and higher (90.7%) when administered subcutaneously. The lower bioavailability following oral administration is due to the first-pass metabolism ( 18 ). Experimental studies conducted in healthy adult Beagle dogs confirmed that maropitant does not have any prokinetic effect ( 29 ). Therefore, the use of maropitant as an antiemetic drug does not affect the process of gastric emptying.

3.3. Maropitant for Uremic Gastritis

Uremic gastritis is defined as the histopathologic changes and gastrointestinal signs that occur due to renal failure in dogs ( 30 ). This condition is commonly associated with acute renal failure or end-stage chronic renal failure ( 22 ). Renal failure-induced uremia can disrupt the integrity of epithelial tight junctions of the stomach, jejunum, ileum, and colon ( 31 ). The histopathological changes associated with uremic gastritis include glandular atrophy, fibroplasia, mast cell infiltration, edema of the lamina propria, submucosal arteritis, and mineralization ( 30 , 32 ). The classical uremic signs, such as vomiting, nausea, and anorexia develop only when azotemia worsens. In addition, such clinical signs are also induced by the effect of uremic toxins on the chemoreceptor trigger zone (CRTZ) ( 32 ). The uremic toxins generated in renal failure patients are sensed by the CRTZ of the area postrema. The ablation of this area in dogs prevented uremic vomiting in dogs ( 33 ).

The high blood concentrations of gastrin are one of the possible mechanisms contributing to gastrointestinal pathology as a result of decreased renal catabolism and loss of inhibitory control over gastrin secretion ( 22 , 34 ). Therefore, high levels of gastrin in the circulation can increase gastric acid secretion. Another proposed mechanism involves the back-diffusion of hydrochloric acid and pepsin into the stomach resulting in inflammation and release of histamine, which further stimulate acid secretion. This mechanism is facilitated by the loss of integrity of the gastric mucosal barrier (pre-epithelial, epithelial, and post-epithelial elements) ( 32 , 35 ). Canine uremic gastropathy affects mucosal lamina propria, and the lesions produced can be linked to diffuse vascular injury and altered parietal cell function ( 36 ). Therefore, efforts have to be directed to correcting dehydration, acid-base, and electrolyte imbalance. In addition, antiemetics, prokinetic agents, H2-receptor antagonists, antacids, gastric protectants, and adsorbents are commonly used to manage the gastrointestinal dysfunction associated with renal failure ( 22 ).

Maropitant has also been demonstrated to have therapeutic efficacy in managing chronic vomiting, other than acute vomiting, in cats with chronic kidney disease ( 23 ). Therefore, maropitant is ideal for the nutritional management of patients with chronic kidney disease. Regarding the broad-spectrum antiemetic activity of maropitant covering both peripheral and central emetogens ( 20 ), it can be recommended for managing uremic vomiting in dogs. Moreover, maropitant is the ideal choice for managing emesis associated with uremia since it has already demonstrated efficacy against xylazine-induced vomiting in cats (36), both of which act via the area postrema ( 33 , 36 , 37 ).

3.4. Perioperative Use of Maropitant

Morphine is commonly administered in the epidural space to obtain long-lasting analgesia during the postoperative period ( 38 ). However, the use of epidural opioids can induce emesis in dogs ( 39 ). Maropitant can prevent vomiting induced by morphine administration (postoperative analgesia) in dogs ( 38 , 40 ). Subcutaneous administration of maropitant (1 mg/kg) 30 min before the intramuscular administration of morphine reduced the frequency of emesis (70% decrease) in dogs undergoing ovariohysterectomy (40). Similar results were obtained when maropitant was used with epidural administration of morphine in dogs ( 38 ). Maropitant can be used as a pre-anesthetic agent for ovariohysterectomy in dogs since it has been found to minimize the systolic arterial pressure and heart rate response to surgical stimulation ( 41 ). It also offered better recovery quality, and the animals are more likely to eat within 3 h post-recovery period (41).

The result of previous studies revealed that maropitant had better antiemetic efficacy than metoclopramide for preventing morphine-induced vomiting in dogs ( 39 ). In addition, maropitant also prevented hydromorphone-induced vomiting in dogs when administered 30-45 min before the opioid ( 12 , 42 ). However, the significant decrease in the incidence of vomiting was not associated with an improvement in the signs of nausea and ptyalism ( 42 ). Dogs treated with maropitant require a slightly lower percentage of isoflurane as an inhalational anesthetic ( 41 ). In addition, although intravenous administration of maropitant decreased the minimum alveolar concentration (MAC) of sevoflurane in dogs ( 43 ), epidural administration did not affect the MAC value ( 43 ). The administration of maropitant also reduced the MAC for blunting adrenergic response of sevoflurane, indicating a sparing effect on the anesthetic requirement in dogs ( 44 ). It decreases the anesthetic requirement during visceral stimulation of the ovary and ovarian ligament. Therefore, NK-1 receptor antagonists play a major role in managing ovarian and visceral pain in dogs ( 45 ). NK-1 receptors are identified in different areas of the pain pathways, including the dorsal horn, dorsal root ganglia, sensory afferents, ascending projections of the spinal cord. Therefore, NK-1 receptor antagonists might be effective for managing visceral pain ( 10 ).

3.5. Side Effects of Maropitant

Subcutaneous administration of maropitant is associated with pain and discomfort in dogs and cats ( 39 , 46 ) (Figure 2). The pain is due to the presence of metacresol, a preservative used in some formulations (Cerenia, Zoetis) ( 46 ). Therefore, another formulation (Prevomax, Le Vet.) was developed that contained benzyl alcohol as the preservative. Maropitant formulations with benzyl alcohol were significantly less painful due to the local anesthetic properties of benzyl alcohol ( 46 ). In addition, subcutaneous injection of refrigerated maropitant (Cerenia) may significantly reduce the pain associated with it ( 47 ).

Figure 2. The mechanism of action and indications of maropitant, a substance P (neurokinin-1) receptor antagonist used as antiemetic in dogs.

4. Conclusion

Gastrointestinal dysfunction associated with renal failure is considered the major challenge during the medical management of canine patients. Therefore, specific nutritional and medical management strategies have to be developed to control and treat such dysfunctions. Substance P (Neurokinin-1 receptor) antagonist, such as maropitant has become the antiemetic of choice in veterinary patients for the prevention of chemotherapy-induced vomiting. In addition, maropitant can be considered an ideal antiemetic in dogs and cats due to its broad-spectrum activity against various emetic stimuli. Therefore, the current evidence indicated the potential use of maropitant for managing emesis associated with canine uremic gastropathy. In addition, the NK1 receptor antagonists may also prove beneficial for chemotherapy-induced nausea and vomiting in dogs. Furthermore, since NK-1 receptors are identified in different areas of the pain pathways, NK-1 receptor antagonists might effectively manage visceral pain. However, further studies are required to confirm the therapeutic potential of NK-1 receptor antagonist drugs, such as maropitant in canine medicine.

Authors' Contribution

Study concept and design: K. S. and S. K. D.

Acquisition of data: K. S. and K. J.

Analysis and interpretation of data: K. S. and K. J.

Drafting of the manuscript: K. S. and K. J.

Critical revision of the manuscript for important intellectual content: M. A., Aakanksha, S. N. C., P. K. P., S. K. D. and K. D.

Administrative, technical, and material support: P. K. P., S. K. D., and K. D.

Conflict of Interest

Authors declare that there exist no commercial or financial relationships among them that could, in any way, lead to a potential conflict of interest regarding the publication of the present study.

Grant Support

The authors did not receive any support from any ornamental, public, or non for profit organization or institutes for the present study. No funding was received to assist researchers with the preparation of this manuscript.

Acknowledgement

The authors are thankful to the Director, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India, for providing the necessary research facilities.

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