Vofopitant

Preclinical pharmacology.

To determine whether blocking substance P signaling attenuates the hypertension and bradycardia evoked by colorectal distension (CRD) in spinal cord injured (SCI) rats.

University laboratory in Pennsylvania, U.S.A.

Tachykinin NK1 receptor antagonists were administered 30 min prior to CRD three weeks after complete spinal cord transection at the 4^th thoracic (T4) level. The dose range, route of administration, and pretreatment time was based on published data demonstrating occupancy of brain NK1 receptors in rodents.

Subcutaneous (SC) administration of 10-30 mg/kg GR205171 ((2S,3S)-N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine dihydrochloride) reduced CRD-induced hypertension and bradycardia by 55 and 49%, respectively, compared with pretreatment values. There was no effect of GR205171 on resting blood pressure or heart rate. In contrast, the same dose range of CP-99,994 ((2S,3S)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine dihydrochloride) had no effect on CRD-induced cardiovascular responses.

The effective dose range of GR205171 to alleviate autonomic dysreflexia is consistent with the blockade of NK1 receptors on pelvic sensory afferents in the lumbosacral spinal cord, which may in turn prevent the over-excitation of sympathetic preganglionic neurons (SPNs) that regulate blood pressure and heart rate. The findings provide preclinical support for the utility of NK1 receptor antagonists to treat autonomic dysreflexia in people with SCI. The difference in the effects of the two NK1 receptor antagonists may reflect the ~200-fold lower affinity of CP-99,994 than GR205171 for the rat NK1 receptor.

Cranial hypersensitivity is a prominent symptom of migraine, exhibited as migraine headache exacerbated with physical activity, and cutaneous facial allodynia and hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms and as a tool to screen therapeutics. We have previously shown that nitroglycerin triggers cranial allodynia in association with migraine-like headache, and this translates to neuronal cranial hypersensitivity in rats. Furthermore, responses in both humans and rats are aborted by triptan administration, similar to responses in spontaneous migraine. Here, our objective was to study the nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically gepants and ditans, for the acute treatment of migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to nitroglycerin, followed by treatment with a calcitonin gene-related peptide receptor antagonist, gepant (olcegepant), a 5-HT1F receptor agonist, ditan (LY344864), and an NK1 receptor antagonist (GR205171). Nitroglycerin induced activation of migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal hypersensitivity. These responses were aborted by olcegepant and LY344864. However, GR205171, which failed in clinical trial for both abortive and preventive treatment of migraine, had no effect. These data support the nitroglycerin model as a valid approach to study cranial hypersensitivity and putative mechanisms involved in migraine and as a screen to dissect potentially efficacious migraine therapeutic targets.