u.9., Hungary 1 Somatostatin (6.11 nmol kg 71 i.p.) inhibited neurogenic plasma extravasation evoked by 1% mustard oil and non-neurogenic oedema induced by 5% dextran in the rat skin. 2 Cyclic synthetic octapeptide (TT-248 and TT-250) and heptapeptide (TT-232) somatostatin analogues proved to be more e ective in reducing neurogenic and non-neurogenic in¯ammatory reactions but octreotide had no in¯uence on either neurogenic or non-neurogenic in¯ammation.

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The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50 -400 M), eperisone, lanperisone, inaperisone, and silperisone (25-200 M) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100 -800 M) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with tolperisone and its analogs in the [3 H]batrachotoxinin A 20-␣-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of tolperisone-type centrally acting muscle relaxant drugs. Furthermore, tolperisone, eperisone, and especially silperisone had a marked effect on voltagegated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that tolperisonetype muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.2-Methyl-1-(4-methylphenyl)-3-(1-piperidinyl)-1-propanone hydrochloride (tolperisone) is an old, centrally acting muscle relaxant drug that is mainly used for treating muscle spasticities of neurological origin and painful muscle spasms due to rheumatologic conditions. Besides being an effective antispastic agent (Pratzel et al., 1996;Dulin et al., 1998), tolperisone also has analgesic activity in rodents (Sakaue et al., 2004) and in humans (Svensson et al., 2003). It possesses relatively few side effects in humans (Dulin et al., 1998). Other propiophenone muscle relaxants include 1-(4-ethylphenyl)-2-methyl-3-(1-piperidinyl)-1-propanone hydrochloride (eperisone), which is also a registered drug (Bose, 1999), and (Ϫ)-2-(R)-methyl-3-(1-pyrrolidinyl)-1-[4-(trifluoromethyl)phenyl]-propanone hydrochloride (lanperisone; Sakitama et al., 1997) and 1-(4-ethylphenyl)-2-methyl-3-(1-pyrrolidinyl)-1-propanone hydrochloride (inaperisone; Morikawa et al., 1992), two agents that had been tested in human phase III studies but not introduced into the clinical practice. 1-[(4-Fluorobenzyl)dimethylsilylmethyl]piperidine hydrochloride (silperisone), a sila analog of tolperisone (Farkas et ...

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The putative anti-inflammatory and anti-nociceptive activity of the heptapeptide somatostatin analogue TT-232 ( D-Phe-Cys-Tyr- D-Thr-Lys-Cys-Thr-NH(2)) was investigated in the rat and mouse, as well as its effect on neuropathic hyperalgesia, gastric ulceration and the release of sensory neuropeptides. In the rat, carrageenin-induced paw oedema was inhibited dose dependently by TT-232 (3x2.5-20 microg/kg i.v.). Evans blue accumulation induced by intraarticular bradykinin injection (0.5 nmol in 0.1 ml) was slightly, but significantly inhibited by a single TT-232 dose (5-20 microg/kg). Cutaneous neutrophil accumulation over a 3-h period after intradermal (i.d.) injection of carrageenin (1 mg/site) or interleukin 1beta (IL-1beta, 3 pmol/site) was inhibited significantly by TT-232 (3x80 microg/kg i.v.), while diclofenac (3x10 mg/kg i.v.) elicited significant inhibition only in the IL-1beta test. In the mouse, TT-232 potently decreased oedema formation induced by 2.5% capsaicin applied topically to the ear. Mechano-nociception in the rat hind-paw during neuropathic pain induced by partial sciatic nerve injury (model of Seltzer) was measured using the Randall-Selitto test. TT-232 (5-20 microg/kg i.p. on the 7th day after the operation) dose-dependently inhibited the mechano-nociceptive hyperalgesia. In vitro release of substance P (SP), calcitonin gene-related peptide (CGRP) and somatostatin from the isolated rat trachea in response to electrical field stimulation (40 V, 0.1 ms, 10 Hz, 120 s) of its nervous elements was inhibited significantly by 500 nM TT-232. The role of G protein-coupled receptors in the effect of TT-232 was indicated by the prevention of its inhibitory action on the release of sensory neuropeptides by incubation the tissue for 1 or 6 h with pertussis toxin (100 ng/ml). The release of sensory neuropeptides to in response to electrical nerve stimulation was not inhibited by a potent tyrosine kinase inhibitor, genistein (50 microM). TT-232 (up to 5 mg/kg i.p.) did not induce mucosal lesions in either the stomach or the duodenum. These data suggest that TT-232, a somatostatin analogue devoid of endocrine effects, is a promising lead molecule in the search for novel, broad-spectrum anti-inflammatory and analgesic agents.