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To elucidate mechanisms of acute and chronic pain, it is important to understand how spinal excitatory systems influence opioid analgesia. The tachykinin substance P (SP) represents the prototypic spinal excitatory peptide neurotransmitter͞neuromodulator, acting in concert with endogenous opioid systems to regulate analgesic responses to nociceptive stimuli. We have synthesized and pharmacologically characterized a chimeric peptide containing overlapping NH2-and COOH-terminal functional domains of the endogenous opioid endomorphin-2 (EM-2) and the tachykinin SP, respectively. Repeated administration of the chimeric molecule YPFFGLM-NH2, designated ESP7, into the rat spinal cord produces opioid-dependent analgesia without loss of potency over 5 days. In contrast, repeated administration of ESP7 with concurrent SP receptor (SPR) blockade results in a progressive loss of analgesic potency, consistent with the development of tolerance. Furthermore, tolerant animals completely regain opioid sensitivity after post hoc administration of ESP7 alone, suggesting that coactivation of SPRs is essential to maintaining opioid responsiveness. Radioligand binding and signaling assays, using recombinant receptors, confirm that ESP7 can coactivate -opioid receptors (MOR) and SPRs in vitro. We hypothesize that coincidental activation of the MOR-and SPR-expressing systems in the spinal cord mimics an ongoing state of reciprocal excitation and inhibition, which is normally encountered in nociceptive processing. Due to the ability of ESP7 to interact with both MOR and SPRs, it represents a unique prototypic, anti-tolerance-forming analgesic with future therapeutic potential.T he neuropeptide substance P (SP) and endogenous opioids are intimately involved in the regulation of acute and chronic pain transmission (1-6). Overlapping distributions of SP-and opioid-containing neurons, as well as their corresponding G protein-coupled receptors, within the superficial dorsal horn of the spinal cord suggest major SP͞opioid functional interactions (7-9). The superficial dorsal horn is an important site of functional integration and transmission of nociceptive input. Here neuronal signaling is mediated by both SP and excitatory amino acids released from primary afferent terminals with further modulation by opioid peptides originating from secondorder spinal cord neurons. In light of the established literature indicating that SP-and opioid-expressing neurons presumably mediate opposite physiological effects at the spinal level, investigators have tended to overlook the role of SP and SP receptors (SPRs) in the regulation of endogenous opioid systems (10-14), particularly in the area of analgesic responsiveness. Previous pharmacological data from our group strongly suggest that SP released in the dorsal horn plays an important role in antinociception by regulating analgesic activity of the postsynaptic opioid systems (15,16). In particular, we demonstrated that low doses of SP, when coadministered with marginally effective doses of morphine sulfa...

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Prior studies in rodents have shown significant depletion of reduced glutathione (GSH) in peripheral organs following acute systemic or central administration of opioids. However, little information exists on whether opioid administration affects concentrations of brain GSH. Recently, clinical observations have indicated acute declines of GSH concentrations in the cerebrospinal fluid of cancer patients after acute intracerebroventricular (ICV) morphine which may contribute to the development of organic behavioral brain syndromes associated with central opioid analgesia. Collectively these data led us to investigate the effect of acute systemic and central morphine on regional concentrations of GSH in rat brain. Systemic morphine had no effect on GSH concentrations in selected brain areas. In contrast, ICV morphine resulted in selective GSH depletion in the caudate nucleus, consistent with concurrent excitatory locomotive behavior. This change may have reflected morphine-induced oxidative stress together with increased metabolic activity within the extrapyramidal system.

SummaryMany years preclinical and clinical anatomic, pharmacologic, and physiologic studies suggest that SP-and opioidexpressing neurons produce opposite biological effects at the spinal level, i.e., nociception and antinociception, respectively. However, in certain circumstances intrathecally administered SP is capable of reinforcing of spinal morphine analgesia and may therefore function as an opioid adjuvant in vivo. The SP dose-response curve of spinally administered SP follows a bell-shaped or inverted-U configuration, permitting pharmacological dissociation of opioid-potentiating and analgesic properties of SP from traditional hyperalgesic effects seen at significantly higher concentrations. This analgesic effect is blocked by naloxone but unaffected by transection of the spinal cord, thus demonstrating the lack of supraspinal modulation. The present report briefly describes both reinforcing and opposing interactions between multiple opioid systems and substance P at the spinal level. We propose that a likely mechanism underlying SP-mediated enhancement of opioid analgesia is the ability of SP to release endogenous opioid peptides within the local spinal cord environment.

Six analogs of leucine-enkephalin were synthesized in which a 1,5-disubstituted tetrazole ring was incorporated in order to lock selected peptide bonds in cis geometry. The obtained compounds were examined based on their biological effects in vivo and in vitro. Only one analog was completely inactive in binding assays being very weakly active in the antinociceptive test. The remaining five compounds displayed at least weak receptor affinity and in vivo activity.

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