ABSTRACT
We have previously shown that young guinea pigs repeatedly exposed to sidestream cigarette smoke (SS) develop decreased airway reactivity of the C-fiber system without changing reactivity to one of its neurotransmitters, substance P (SP). This study was designed to determine whether the decreased reactivity was due to decreased responsiveness to another neurotransmitter, neurokinin A (NKA), decreased lung SP content, decreased affinity or number of NK1 receptors, and/or decreased number of C-fibers. Duncan Hartley guinea pigs were exposed to filtered air (FA) or to SS for 6 h/day, 5 days/week for 5 weeks starting at 1 week of age. SS exposure did not change, (1) airway reactivity to NKA injected into the pulmonary artery of their isolated perfused lungs (n = 6-7 each group), (2) lung SP content as measured by enzyme immunoassay (n = 12 each group), (3) NK1 receptor number or affinity as measured by radioligand binding (n = 7 each group), or (4) SP-immunoreactive nerve profiles of the terminal bronchioles or small airways (n = 6 each group). Thus, SS exposure does not decrease C-fiber system by reducing NKA responsiveness, decreasing SP content, changing NK1 receptors, or decreasing the number of C-fibers.
Subject(s)
Nerve Fibers/drug effects , Neurokinin A/toxicity , Tobacco Smoke Pollution/adverse effects , Air Pollution, Indoor , Airway Resistance/drug effects , Analysis of Variance , Animals , Bronchi/drug effects , Bronchi/metabolism , Guinea Pigs , Immunoenzyme Techniques , Immunohistochemistry , In Vitro Techniques , Injections, Intra-Arterial , Lung/drug effects , Lung/metabolism , Male , Nerve Fibers/metabolism , Neurokinin A/administration & dosage , Pulmonary Artery/drug effects , Radioligand Assay , Substance P/metabolismABSTRACT
Aerosol administration of neurokinin A (NKA) or substance P (SP) to conscious guinea pigs produced labored abdominal breathing (dyspnea). Time to onset of dyspnea was inversely related to tachykinin concentration. Aerosol administration of the neutral endopeptidase inhibitor thiorphan significantly potentiated tachykinin-induced dyspnea without affecting responses to leukotriene D4 (LTD4), carbachol, histamine, platelet activating factor or serotonin (5-HT), indicating selectivity for tachykinins rather than a nonspecific effect on agonist reactivity. The rank order of potency for producing dyspnea was LTD4 greater than or equal to NKA (with thiorphan) much greater than SP (with thiorphan) greater than 5-HT = carbachol greater than histamine greater than platelet-activating factor. Pretreatment with propranolol, phentolamine, methysergide, pyrilamine or the peptide leukotriene antagonist, ICI 198,165, did not alter dyspnea induced by NKA or SP. The dose-response curves for NKA and SP were shifted to small degrees (less than 3-fold) to the right by atropine and to the left by indomethacin. Also, pretreatment with capsaicin did not affect responses to NKA or SP, indicating that they do not cause dyspnea by activating capsaicin sensitive C-fibers. These results suggest primarily direct effects of NKA and SP. This model may be useful for in vivo evaluation of tachykinin antagonists.
Subject(s)
Dyspnea/chemically induced , Neurokinin A/toxicity , Substance P/toxicity , Aerosols , Animals , Drug Interactions , Guinea Pigs , Male , Neurokinin A/administration & dosage , SRS-A/pharmacology , Substance P/administration & dosage , Thiorphan/pharmacologyABSTRACT
The effect of neurokinin A (NKA), substance P (SP) and calcitonin gene-related peptide (CGRP) in peripheral hyperalgesia was studied in rats using a modification of the Randall-Selitto paw test. NKA was 10 times more potent than SP which was 500 times more potent than CGRP in inducing hyperalgesia in the rat paw, suggesting that NKA and SP but not CGRP could have an important role in acute hyperalgesic conditions. Furthermore, sensitization induced by several injections of subthreshold doses of NKA or CGRP suggest that these neuropeptides along with SP could participate as mediators or modulators of chronic pain.
Subject(s)
Calcitonin Gene-Related Peptide/toxicity , Hyperalgesia/chemically induced , Neurokinin A/toxicity , Substance P/toxicity , Animals , Inflammation , Male , Nociceptors/drug effects , Nociceptors/physiology , Rats , Rats, Inbred Strains , Substance P/analogs & derivatives , Substance P/antagonists & inhibitors , Substance P/pharmacologyABSTRACT
Neurokinin A (NKA), substance P (SP) and the two peptides combined (SP + NKA) were injected intracutaneously on the forearm and into the temporal muscle of healthy volunteers. Pain intensity, cutaneous wheal and flare responses and tenderness of the temporal muscle were quantitated. SP but not NKA induced cutaneous pain. This relates the algesic effect of SP to the specific N-terminal amino acid sequence of the peptide, not shared by NKA. NKA, however, potentiated the algesic effect of SP as SP + NKA induced a significantly prolonged cutaneous pain sensation. Both peptides induced wheals, but only SP induced flare. These results confirm previous studies relating wheal formation to the identical C-terminal amino acid sequence of the two peptides and flare reaction to the N-terminal part of SP. Injections into the temporal muscle did not cause pain or tenderness.
