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Intrathecal (i.t.) administration into mice of N-ethylmaleimide (NEM), a cysteine protease inhibitor, produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by NEM was inhibited by the intraperitoneal injection of morphine. We have recently reported that dynorphin A and, more potently big dynorphin, consisting of dynorphins A and B, produce the same type of nociceptive response whereas dynorphin B does not [Tan-No K, Esashi A, Nakagawasai O, Niijima F, Tadano T, Sakurada C, Sakurada T, Bakalkin G, Terenius L, Kisara K. Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-d-aspartate receptor mechanism. Brain Res 2002;952:7-14]. The NEM-induced nociceptive behavior was inhibited by pretreatment with dynorphin A- or dynorphin B-antiserum and each antiserum also reduced the nociceptive effects of i.t.-injected synthetic big dynorphin. The characteristic NEM-evoked response was not observed in prodynorphin knockout mice. Naloxone, an opioid receptor antagonist, had no effects on the NEM-induced behavior. Ifenprodil, arcaine and agmatine, antagonists at the polyamine recognition site on the N-methyl-D-aspartate (NMDA) receptor ion-channel complex, and MK-801, an NMDA ion-channel blocker inhibited the NEM-induced effects. Ro25-6981, an antagonist of the NMDA receptor subtype containing NR2B subunit was not active. NEM completely inhibited degradation of dynorphin A by soluble and particulate fractions of mouse spinal cord. Collectively, the results demonstrate that endogenous prodynorphin-derived peptides are pronociceptive in uninjured animals, and required for the NEM-induced behavior. The NEM effects may be mediated through inhibition of the degradation of endogenous dynorphins, presumably big dynorphin that in turn activates the NMDA receptor ion-channel complex by acting on the polyamine recognition site.

A series of 37 patients with chronic pain was investigated with regard to neurologic and psychiatric variables. Twenty of the patients were classified as having mainly organic (= somatogenic) pain syndromes while 17 patients were rather suffering from psychogenic pain syndromes. Samples of lumbar cerebrospinal fluid (CSF) were obtained from the patients and analyzed for the presence of opiate receptor-active material, here called endorphins. Patients classified as having mainly organic pain syndromes were found to have significantly lower endorphin levels than patients with predominantly psychogenic pain syndromes. In the total group of patients as well as in the two subgroups, there was a significant correlation between CSF endorphin levels and the depth of depressive symptomatology as reported by the patients. On the other hand, there was no correlation between CSF endorphin levels and extent of anxiety or motor retardation. It is concluded that CSF endorphins reflect central processes involved in chronic pain syndromes.

In 45 consecutive patients with chronic pain syndromes endorphins, fraction I of the cerebrospinal fluid and pain measures by means of electric stimulation via saline electrodes were investigated. In patients with high levels of fraction I (above median) pain threshold, PT and tolerance level, TL, in condition C (continuous stimulation increase) were found to be significantly higher than in patients with low levels of fraction I (below median). The results indicate that the endorphins are one of the physiological factors that contribute to the pain threshold and the tolerance level.