Several reports in the literature have suggested that dynorphin- A-(1-13) (dyn) experts a modulatory effect on mu opioid pharmacodynamics. Dyn is an endogenous opioid peptide with selective affinity for kappa opioid receptors. It has been shown that dyn inhibits both morphine (mu)-induced increases in EEG spectral power and morphine-induced suppression of slow-wave sleep in non-tolerant rats, and enhances both of these responses in morphine-tolerant rats. In addition, EEG power spectra, obtained after morphine administration in non-tolerant rats treated 24 hr earlier with dyn + morphine, were qualitatively similar to those EEG power spectra previously obtained after acute administration of kappa opioids. Furthermore, twenty-four hr after dyn + morphine treatment in non-tolerant rats, morphine produced diuresis, which is a characteristic kappa opioid affect, whereas morphine is usually antidiuretic. Several observed interactions between ethylketocyclazocine and morphine may also be indicative of kappa opioid-induced modulation of mu opioid effects. The modulatory effects of dyn and other kappa opioids on mu opioid effects. The modulatory effects of dyn and other kappa opioids on mu opioid-induced effects may have important applied implications. It seems important that these modulatory effects be extensively studied and assessed. Thus, in non- tolerant rats, modulatory effects of dyn on morphine and possible modulatory effects of dyn on kappa opioids will be studied as a function of dose. In morphine-tolerant rats, modulatory effects of dyn will be assessed as a function of time and dose. Possible dyn modulation of morphine dependence will be studied, using acute versus chronic dyn administration. Furthermore, possible dyn modulation of long-term, stress-induced tolerance to morphine effects will be studied. Also, rats will be given chronic morphine + kappa opioid treatment in order to assess possible modulatory effects of kappa opioids on the degree and time-course of tolerance development to morphine effects, and on the state of morphine dependence. Further studies of kappa opioid modulation of mu opioid effects should contribute to the basic, as well as applied, understanding of opioid pharmacodynamics and pharmacokinetics.
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