Neurokinin-1 Receptor Blockade Research Articles

5-Hydroxytryptamine (5-HT)1A Autoreceptor Adaptive Changes in Substance P (Neurokinin 1) Receptor Knock-Out Mice Mimic Antidepressant-Induced Desensitization

Antagonists at substance P receptors of the neurokinin 1 (NK1) type have been shown to represent a novel class of antidepressant drugs, with comparable clinical efficacy to the selective serotonin (5-HT) reuptake inhibitors (SSRIs). Because 5-HT(1A) receptors may be critically involved in the mechanisms of action of SSRIs, we examined whether these receptors could also be affected in a model of whole-life blockade of NK1 receptors, i.e. knock-out mice lacking the latter receptors (NK1-/-). 5-HT(1A) receptor labeling by the selective antagonist radioligand [(3)H]N-[2-[4-(2-methoxyphenyl)1-piperazinyl]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide (WAY 100635) and 5-HT(1A)-dependent [(35)S]GTP-gamma-S binding at the level of the dorsal raphe nucleus (DRN) in brain sections, as well as the concentration of 5-HT(1A) mRNA in the anterior raphe area were significantly reduced (-19 to -46%) in NK1-/- compared with NK1+/+ mice. Furthermore, a approximately 10-fold decrease in the potency of the 5-HT(1A) receptor agonist ipsapirone to inhibit the discharge of serotoninergic neurons in the dorsal raphe nucleus within brainstem slices, and reduced hypothermic response to 8-OH-DPAT, were noted in NK1-/- versus NK1+/+ mice. On the other hand, cortical 5-HT overflow caused by systemic injection of the SSRI paroxetine was four- to sixfold higher in freely moving NK1-/- mutants than in wild-type NK1+/+ mice. Accordingly, the constitutive lack of NK1 receptors appears to be associated with a downregulation/functional desensitization of 5-HT(1A) autoreceptors resembling that induced by chronic treatment with SSRI antidepressants. Double immunocytochemical labeling experiments suggest that such a heteroregulation of 5-HT(1A) autoreceptors in NK1-/- mutants does not reflect the existence of direct NK1-5-HT(1A) receptor interactions in normal mice.

Segmental effect of spinal NK-1 receptor blockade on the pressor reflex.

The physiological effects of substance P (SP) are mediated via activation of neurokinin-1 (NK-1) receptors. The purpose of this study was to test the hypothesis that blockade of NK-1 receptors in the dorsal horn, both at the site of entry for the primary afferent neurons and adjacent spinal segments, attenuates the pressor reflex evoked by static contraction and stretch of skeletal muscle. Cats were anesthetized with alpha-chloralose and urethan, and a laminectomy was performed. With the exception of the L7 dorsal root, the dorsal and ventral roots from L5 to S2 were sectioned on one side of the spinal cord. Thus the primary afferent fibers mediating the pressor reflex enter the spinal cord via the L7 dorsal root in these experiments. Based on dose-response data, dialysis of the NK-1 receptor antagonist CP-96,345 (5 mM for 2 h) into the L7 dorsal horn ipsilateral to the contracting muscle attenuated the pressor response to static contraction (75 +/- 15 vs. 46 +/- 7 mmHg; n = 5 cats) but not muscle stretch (60 +/- 12 vs. 50 +/- 8 mmHg). Administration of the inactive enantiomer of CP-96,345, CP-96,344 (5 mM for 2 h), into the L7 dorsal horn failed to alter the cardiovascular changes elicited by contraction (45 +/- 7 vs. 43 +/- 6 mmHg) and stretch (31 +/- 8 vs. 32 +/- 11). Dialysis of 5 mM CP-96, 345 into the dorsal horn at the L6 and S1 segments for 2 h decreased the peak pressor response to static contraction (58 +/- 9 vs. 31 +/- 6 mmHg; n = 7) and muscle stretch (61 +/- 6 vs. 44 +/- 8 mmHg). These data suggest that the activation of NK-1 receptors, both at the site of entry and in regions outside of the entry site for afferent neurons, is involved in the spinal processing that produces the pressor reflex evoked by static contraction of skeletal muscle.

Sidestream smoke exposure enhances rapidly adapting receptor responses to substance P in young guinea pigs.

We determined the effect of sidestream tobacco smoke (SS) exposure on responses of lung rapidly adapting receptors (RARs), peak tracheal pressure (Ptr), and arterial blood pressure (ABP) to substance P in young guinea pigs. Guinea pigs were exposed to SS or filtered air from day 8 to days 41-45 of life. They were then anesthetized and given three doses of intravenous substance P (1.56-4.94 nmol/kg). SS exposure augmented substance P-evoked increases in RAR activity (P = 0.029 by analysis of variance) but not substance P-evoked increases in peak Ptr or decreases in ABP. Neurokinin 1-receptor blockade (CP-96345, 400 nmol/kg) attenuated substance P-evoked increases in RAR activity (P = 0.001) and ABP (P = 0.009) but not in peak Ptr (P = 0.06). This chronic exposure to SS in young guinea pigs exaggerates RAR responsiveness to substance P. The findings may help explain the increased incidence of airway hyperresponsiveness and cough in children chronically exposed to environmental tobacco smoke.