Antinociceptive effects in mice after intrathecal injection of a substance P receptor antagonist, Spantide: lack of 'neurotoxic' action.

The present investigation was undertaken to determine the antinociceptive potency and possible neurotoxic effects of a substance P (SP) receptor antagonist, [D-Arg,D-Trp,Leu]SP (Spantide), after intrathecal injection in mice. After the nociceptive tests had been carried out, the animals were sacrificed and the spinal cords were investigated for histopathological changes, since such have been reported previously to occur in rats. It was found that the reaction latency in the tail-flick test increased in the dose range 0-10 micrograms. The effect was maximal at 10 and 45 min after 10 micrograms Spantide, and somewhat lower when 5 micrograms was used. None of the animals showed the complete motor impairment reported previously to occur after intrathecal administration in rats. In some of the mice we observed a slight rigidity in the hind-legs. At histopathological examination, it was found that Spantide produced no histological changes indicative of 'neurotoxic' effects. In agreement with this, the immunohistochemical evaluation, using calcitonin gene-related peptide (CGRP) as a marker for motoneurons and central branches of primary sensory neurons, did not provide evidence that the intrathecal injection of 10 micrograms Spantide produced any effects when compared to vehicle-injected animals. In conclusion, the present results demonstrate an antinociceptive effect of Spantide when injected intrathecally in mice, and that this occurred without any signs of toxic reactions in spinal cord as previously has been reported for the rat.

Antinociceptive and neurotoxic actions of substance P analogues in the rat's spinal cord after intrathecal administration.

Intrathecal administration of both (D-Pro2,D-Trp7,9)-substance P (DPDT) and (D-Arg1,D-Trp7,9,Leu11)-substance P (DADTL) elicited antinociception in hot-plate and tail-flick test, with DADTL as the most potent. The animals injected with 2.0 micrograms DADTL, and several animals administered with DPDT at the same dose, developed bilateral motor blockade of the hind-legs, persisting for up to 3 days after DADTL. The effect of DPDT appeared to be reversible at this dose. On histopathological examination it was found that these animals with persistent paralysis had widespread neuronal necrosis in the lumbar region of the spinal cord. It is concluded that the peptides have antinociceptive effects after the intrathecal administration in rats, but that there is a small margin between the dose producing this effect and that causing irreversible toxic reactions in the spinal cord.

Importance of particulate antigen for the induction of dual bronchial reaction in guinea-pigs.

There has been a lack of small animal models for the secondary allergic response (SAR) seen after bronchial challenge in many asthmatic patients. We have found that challenge with particulate instead of soluble antigen will provoke an SAR-like bronchial obstruction in the guinea-pig. The particulate form was obtained by coupling the antigen covalently to Sepharose beads (approximately 100 microns). Different experiments suggest that SAR is obtained only when the challenge is induced via IgE-mediated mechanisms and when the antigen is sufficiently large to provoke frustrated phagocytosis by the invading inflammatory cells. As judged in lungs sections SAR was related to bronchiolitis.