spinorphin and Pain

It is possible that enkephalins are involved in the pain-modulating mechanism in the spinal cord. Enkephalins, however, are short-lived, being rapidly degraded by various endogenous enzymes. Many substances that inhibit enkephalin-degradation have been investigated and it has been reported that some inhibitors (e.g. kelatorphan and RB101) alone showed anti-nociceptive activity. We found an endogenous factor that modulated enkephalin-degrading activity and purified it from bovine spinal cord based on its inhibitory activity toward enkephalin-degrading enzymes. Structural analysis revealed the factor to be Leu-Val-Val-Tyr-Pro-Trp-Thr and it was named spinorphin. It has been found that spinorphin inhibited the activity toward various enkephalin-degrading enzymes from monkey brain, especially dipeptidyl peptidase III (DPPIII, Ki=5.1 x 10(-7) M). Recently we reported that this inhibitor significantly inhibited bradykinin (BK)-induced nociceptive flexor responses. Importantly, the mode of inhibition to BK-responses by spinorphin was different from the case with morphine. The morphine-induced blockade of BK-response was attenuated by pertussis toxin treatment, whereas that of spinorphin was not. We also have reported roles for spinorphin in inflammation. Spinorphin significantly inhibited the functions of polymorphonuclear neutrophils (PMNs) by suppressing the binding of fMLF to its receptor on PMNs. Further, this inhibitor suppressed the carrageenan-induced accumulation of PMN in mouse air pouches after intravenous administration. These results indicate that spinorphin may be an endogenous anti-inflammatory regulator. The possible role of spinorphin and its analog as regulators in pain and inflammation will be discussed.

Topics: Aminopeptidases; Animals; Anti-Inflammatory Agents; Enzyme Inhibitors; Hemoglobins; Humans; Inflammation; Neutrophils; Oligopeptides; Pain; Peptide Fragments

In the course of elucidating physiological roles of spinorphin, an endogenous regulator of enkephalin-degrading enzyme, we found that dipeptidyl peptidase III (DPP III) was contained in human cerebrospinal fluid (CSF). In this study, we examined the activity of DPP III in human CSF derived from patients with pain.. We used human CSF as specimen collected during operations under spinal anesthesia. Patients were divided into three groups, patients without pain (normal group), with acute pain, and with chronic pain. We measured DPP III activities in each group, using specific substrates, such as Arg-Arg-AMC.. DPP III activity for human CSF in patients with acute pain was significantly lower compared with that in patients without pain (P < 0.05). Furthermore, DPP III activity correlated with APN activity, another spinorphin-degrading enzyme, in patients with pain (r = 0.444).. These results indicate that DPP III may play a role in regulation of endogenous opioids, leading to pain modulation.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Chronic Disease; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Female; Humans; Male; Middle Aged; Oligopeptides; Pain; Reference Values

We found that spinorphin, a novel neuropeptide showed analgesia in a different manner compared with morphine. By measuring flexor responses induced by the intraplanter injection of substances, the presence of three different types of sensory neurons were demonstrated. Although spinorphin completely blocked 2-metylthioadenosine (2-MeS ATP, a P2X(3) agonist)-induced responses, morphine did not. On the other hand, morphine-induced blockade of bradykinin (BK, a B(2)-receptor agonist)-responses was attenuated by pertussis toxin (PTX) treatment, whereas that of spinorphin was not. Thus it is suggested that spinorphin has a spectrum of analgesia which covers the blockade of nociception insensitive to morphine.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Adenosine; Analgesics, Opioid; Animals; Animals, Newborn; Bradykinin; Capsaicin; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Mice; Morphine; Neurons, Afferent; Neuroprotective Agents; Oligopeptides; Pain; Pertussis Toxin; Piperidines; Protease Inhibitors; Purinergic Agonists; Thionucleosides; Time Factors; Virulence Factors, Bordetella