enkephalin-met--ala(2)- and Pain

Topics: Amino Acids; Analgesia; Animals; Enkephalin, Methionine; gamma-Aminobutyric Acid; Humans; Male; Motor Activity; Movement Disorders; Pain; Rats; Taurine

To clarify the properties of BL-2401 ((+/-)-3-[2-benzyl-3-(propionylthio) propionyl]amino-5-methylbenzoic acid), a novel enkephalinase inhibitor, we examined its antinociceptive and antidepressant-like activities after oral administration, along with their association with endogenous opioid systems. BL-2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writhing test (ED50: 12.4 mg/kg) and the rat acetic acid writhing test (ED50: 55.8 mg/kg), the antinociceptive effect being antagonized by naloxone hydrochloride. BL-2401 also relieved arthritis-induced hyperalgesia in rats. In the mouse hot-plate and tail pressure tests, BL-2401 showed significant but modest antinociception at higher doses (200 and 400 mg/kg). In addition, BL-2401 (100 mg/kg) produced a naloxone-reversible antidepressant-like effect in the mouse forced swimming test. As for the mechanism of the action, the active metabolite of BL-2401, BL-2240 ((+/-)-3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid), selectively inhibited enkephalinase in vitro (IC50: 5.2 nM). Oral administration of BL-2401 to mice significantly inhibited the enkephalinase activity in the striatum and also potentiated the antinociceptive effect of (D-Ala2,Met5)-enkephalin given intracisternally. These findings indicate that BL-2401 is an orally active enkephalinase inhibitor and may produce antinociceptive and antidepressant-like effects in association with endogenous opioid systems.

Topics: Administration, Oral; Analgesics; Analgesics, Opioid; Animals; Antidepressive Agents; Benzoates; Benzoquinones; Corpus Striatum; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; Enkephalin, Methionine; Female; Hyperalgesia; Male; Mice; Naloxone; Narcotic Antagonists; Narcotics; Neprilysin; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sulfhydryl Compounds; Swimming

High-dose microinjections of morphine sulfate (15 micrograms) and (D-Ala2)-Met-enkephalin (30 micrograms) were made into the ventral periaqueductal gray of rats. Consistent with previous reports using lower doses, both opiates produced hypoalgesia for noxious thermal stimuli applied to the upper and lower body. More hypoalgesia was observed on the face than on the hind legs or tail. Current thresholds of aversive reaction to stimulation in the trigeminal subnucleus caudalis were unaffected by microinjection of either opiate. Systemic injections of 6 mg/kg morphine sulfate profoundly inhibited defense responses to peripheral noxious stimuli and significantly elevated aversive reaction thresholds for stimulation in the trigeminal subnucleus caudalis. Aversive reactions to stimulation in the dorsal periaqueductal gray remained unaffected by either microinjected or systemically administered opiates.

Topics: Animals; Enkephalin, Methionine; Hot Temperature; Male; Morphine; Pain; Periaqueductal Gray; Rats; Reticular Formation; Sensory Thresholds; Trigeminal Nucleus, Spinal

The systemic administration of subanalgesic doses of [D-Ala2, D-Leu5]enkephalin significantly potentiated the analgesia elicited in rats or mice by intraventricular injection of substance P. On the contrary, systemic administration of low doses of [D-Ala2,Met5]enkephalinamide antagonized the substance P-induced analgesia. The results support the notion of different physiological functions for the enkephalins and suggest an integrated role for enkephalins and substance P in the control of pain at supraspinal levels.

Topics: Animals; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalin, Methionine; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Pain; Rats; Rats, Inbred Strains; Substance P