Dynorphins are endogenous neuropeptides that were discovered in 1982 by Chavkin et al. (1982)
. The dynorphins (dynorphin A, dynorphin B and alpha-neodynorphin) are part of the endogenous opioid system that includes several receptor types: mu, delta, kappa, and NOP, and several endogenous peptides: beta-endorphin and enkephalins (preferentially bind to mu and delta receptors), endomorphins (selectively bind to mu receptors), dynorphins (selectively bind to kappa receptors), and nociceptin (selectively binds to NOP) (Corbett et al., 2006
; Dhawan et al., 1996
; IUPHAR, 2008
). A number of stressors, including intermittent footshock, activate the endogenous opioid systems (Akil et al., 1984
; Amit and Galina, 1986
). Thus, in an early neuropharmacological study on stress-induced reinstatement, Shaham and Stewart (1996)
examined the effect of naltrexone (a preferentially mu
opioid receptor antagonist, 1 or 10 mg/kg) on this reinstatement. They found that even the high dose of naltrexone (10 mg/kg), that should have blocked mu, kappa and delta opioid receptors (Goldstein and Naidu, 1989
), and that decreased heroin priming-induced reinstatement, had no effect on footshock-induced reinstatement of heroin seeking. Additionally, chronic delivery (via minipumps) of heroin or other mu opioid receptor agonists (methadone, buprenophine [also a kappa receptor antagonist]), that occupy the mu opioid receptors and prevent acute receptor activation by stress exposure, had no effect on footshock-induced reinstatement of heroin or cocaine seeking (Leri et al., 2004
; Shaham et al., 1996
; Sorge et al., 2005
). Together, these findings suggest that the putative activation of endogenous opioid systems by footshock is not involved in reinstatement of drug seeking induced by this stressor.
However, results from several studies suggest a role of dynorphins and the kappa opioid receptor in stress-induced reinstatement of drug seeking. Beardsley et al. (2005)
reported that systemic injections of JDTic (a kappa receptor antagonist) attenuated footshock-induced reinstatement of cocaine seeking. The data from this study, however, are difficult to interpret for several reasons: 1) baseline extinction responding differed between the groups tested with the different doses of JDTic; 2) the effect of JDTic on reinstatement of lever responding in the absence of footshock was not assessed; and 3) at the highest dose, JDTic strongly potentiated cocaine-priming-induced reinstatement.
More recently, Chavkin, McLaughlin and colleagues have provided more convincing evidence for a role of dynorphins and kappa opioid receptors in stress-induced reinstatement. These investigators used a CPP reinstatement procedure in mice. In one study, Carey et al. (2007)
reported that systemic injections of arodyn (a kappa receptor antagonist) decreased forced-swim-induced reinstatement of cocaine CPP. In another study, Redila and Chavkin (2008)
reported that systemic injections of nor-BNI (a long-acting kappa receptor antagonist) decreased footshock- and forced-swim-stress-induced reinstatement, and that footshock was ineffective in mice lacking either kappa opioid receptors or prodynorphin. In addition, they showed that injections of U50,488 (a kappa opioid agonist), a drug that induces CRF-dependent stress-like aversive responses (Land et al., 2008
), reinstated cocaine CPP in mice, providing further evidence for a role of dynorphin and kappa opioid receptors in stress-induced reinstatement. Additionally, Valdez et al. (2007)
reported that injections of spiradoline and enadoline (kappa receptor agonists) reinstated cocaine seeking in monkeys. These results are somewhate difficult to interpret in the context of the role of dynorphin/kappa receptors in stress-induced reinstatement, because the reinstating effects of spiradoline and enadoline were blocked by CP154,526 (a CRF1 receptor antagonist) and clonidine (an alpha2-adrenoceptor agonist), but not by nor-BNI (the prototypical kappa receptor antagonist).