sch-32615 and Pain

SCH-32615 is a new enkephalinase inhibitor whose analgesic effects were examined following its stereotactic microinjection into the periaqueductal gray (PAG) and the ventromedial medulla (VMM) regions of the brainstem of the rat. SCH-32615 produced a strong, dose-dependent, naloxone-reversible analgesia to thermal noxious stimuli as measured by the hot plate test (HP; supraspinal analgesia) and the tail flick test (TF; spinal analgesia). The peak analgesic effect was seen within 10 min and remained for 45-60 min. ED50 were for PAG, HP = 10.7 micrograms and TF = 17.3 micrograms, and for VMM, HP = 5.7 micrograms and TF = 7.2 micrograms. Using the irreversible mu receptor antagonist, beta-funaltrexamine, it was found that the endogenous enkephalins in the PAG produce their analgesic effects by acting at only one receptor subtype (the mu receptor) while in the VMM both mu and delta opioid receptors are involved (not through the delta alone as previously believed).

Topics: Animals; Brain Stem; Dipeptides; Dose-Response Relationship, Drug; Medulla Oblongata; Microinjections; Naloxone; Naltrexone; Neprilysin; Pain; Periaqueductal Gray; Rats

The local effects of SCH-32615, an inhibitor of enkephalinase (EC 3.4.24.11) on the hot-plate (HP) and tail-flick (TF) responses were examined following unilateral intracerebral microinjection into the periaqueductal brain (PAG), the medial ventral medulla (VM) and bilateral microinjection into the amygdala (AM) of the rat. In the PAG and VM, SCH-32615 resulted in a dose-dependent increase in HP and TF response latencies over a dose range of 1-30 micrograms with the ED50 values (micrograms) being PAG-TF = 17; PAG-HP = 11; VM-TF = 7; VM-HP = 6. In the AM, dose-dependent increases were only observed on the HP. (ED50 (micrograms) HP = 17). Peak effects were observed within 10 min and response latencies remained elevated for 45-60 min. Injections of SCH-32615 at sites outside of the PAG or VM were considerably less effective. All antinociceptive effects were antagonized by naloxone (1 mg/kg, i.p.). Twenty-four hours following the microinjection of beta-funaltrexamine (an irreversible opioid antagonist) into the PAG or the VM, the effects of SCH-32615 in the PAG were virtually abolished while in the VM, its effects were only moderately reduced. These data suggest that in the presence of a strong thermal stimulus, the behavioral response is subject to a tonically active or stimulus-evoked modulation by the local release in the PAG, VM and AM of an agent, presumably an enkephalin peptide, the degradation of which is altered by enkephalinase inhibition.

Topics: Amygdala; Analgesics; Animals; Dipeptides; Dose-Response Relationship, Drug; Hot Temperature; Male; Medulla Oblongata; Microinjections; Neprilysin; Pain; Periaqueductal Gray; Rats; Rats, Inbred Strains; Reflex

The presence of opioid receptors and enkephalin-releasing neurons in the spinal dorsal horn prompted us to examine whether an enkephalinase inhibitor, SCH32615, given intrathecally would alter the response of the rat on several nociceptive endpoints: 49 degrees C hot plate (HP), 52 degrees C HP; tail flick (TF) and the paw pressure (PP) test. SCH (16-320 nmol, i.t.) resulted in a submaximal dose-dependent increase in the 49 degrees C HP, 52 degrees C HP, TF, and PP measures with the respective ED50 values being 40, 74, 68 and 83 nmol, respectively. AT 320 nmol, no additional increment in effect was observed. Concurrent examination of the effects of 0.1-10 nmol morphine on the 49 degrees C HP, 52 degrees C HP, TF and PP measures revealed i.t. ED50 values of 0.2, 0.8, 0.9 and 0.6 nmol, respectively, with the maximum dose leading to a complete block on all measures. The effects of SCH were totally reversed by naloxone (1 mg/kg, i.p.), a dose which had no detectable effect upon baseline nociceptive response measures. The effects of SCH, even at the highest dose were not accompanied by motor dysfunction or catalepsy. These results are consistent with the hypothesis that high-threshold thermal and mechanical stimuli will evoke the release of an opioid in the spinal space, the metabolism of which is significantly influenced by enkephalinase inhibition.

Topics: Analgesics; Animals; Dipeptides; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hot Temperature; Injections, Spinal; Male; Morphine; Naloxone; Neprilysin; Pain; Rats; Rats, Inbred Strains; Sensory Thresholds; Spinal Cord