James W. Lewis

Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth

Exposure to stress has been associated with alterations in both immune function and tumor development in man and laboratory animals. In the present study, we investigated the effect of a particular type of inescapable footshock stress, known to cause an opioid mediated form of analgesia, on survival time of female Fischer 344 rats injected with a mammary ascites tumor. Rats subjected to inescapable footshock manifested an enhanced tumor growth indicated by a decreased survival time and decreased percent survival. This tumor enhancing effect of stress was prevented by the opiate antagonist, naltrexone, suggesting a role for endogenous opioid peptides in this process. In the absence of stress, naltrexone did not affect tumor growth.

The opioid/nonopioid nature of stress-induced analgesia and learned helplessness.

Exposure to a variety of stressors produces a subsequent analgesic reaction. This stress-induced analgesia (SIA) is sometimes opioid in nature (reversed by opiate antagonists and cross-tolerant with morphine) and sometimes nonopioid. Both 30 min of intermittent footshock and 60-80 five-sec tailshocks have been shown to produce opioid SIA, whereas 3 min of continuous footshock and 5-40 tailshocks produce nonopioid SIA. We report that both of the opioid SIA procedures produce a learned helplessness effect as assessed by shuttlebox escape acquisition and an analgesia that is reinstatable 24 hr. later. The nonopioid procedures produce neither a learned helplessness effect nor a reinstatable analgesia. It is argued that these data implicate the learning of uncontrollability in the activation of opioid systems.

Effects of footshock stress and morphine on natural killer lymphocytes in rats: studies of tolerance and cross-tolerance

Exposure to a form of footshock stress known to cause opioid-mediated analgesia suppresses the cytotoxic activity of natural killer (NK) cells in rats. This suppression is blocked by the opioid antagonist, naltrexone and is mimicked by morphine administration, suggesting mediation by opioid receptors. Supporting this hypothesis, we now report that the morphine-induced suppression of NK activity shows tolerance after 14 daily injections. The NK-suppressive effect of stress, however, shows neither tolerance with repetition nor cross-tolerance in morphine-tolerant rats.

Opioid and non-opioid mechanisms of stress analgesia: lack of cross-tolerance between stressors.

Qualitatively different analgesic responses can be evoked in rats by exposure to prolonged, intermittent or brief, continuous footshock stress. These two forms of stress analgesia appear to be mediated by opioid and nonopioid pain-inhibitory substrates, respectively. The present study confirms our previous observation that tolerance develops to only the opioid form of stress analgesia and shows that cross-tolerance does not occur between the opioid and nonopioid forms. These data provide further evidence that independent mechanisms underlie opioid and nonopioid stress analgesia.

Opioid and non-opioid mechanisms of footshock-induced analgesia: Role of the spinal dorsolateral funiculus

Exposure to inescapable footshock causes either an opioid or non-opioid mediated analgesia in the rat depending on the temporal parameters of its administration. Lesions of the spinal dorsolateral funiculus significantly reduce both the opioid and non-opioid forms of this footshock-induced analgesia. Thus, these two neurochemically discrete pain-inhibitory systems appear to depend on the integrity of the same descending path, one known to be activated by morphine and by analgesic brain stimulation.

Involvement of central muscarinic cholinergic mechanisms in opioid stress analgesia

Stress has been shown capable of differentially activating opioid- and non-opioid-mediated endogenous analgesia systems. In this study, the muscarinic cholinergic antagonist, scopolamine, but not the centrally inactive methylscopolamine, blocks opioid, but not non-opioid stress analgesia. Additionally, naltrexone, an opiate antagonist, attenuates analgesia induced by oxotremorine, a cholinergic agonist. These findings support the existence of a muscarinic cholinergic synapse in a central nervous system opioid pain-inhibitory pathway.

Morphine analgesia: enhancement by shock-associated cues

Recent research has shown that rats exposed to repeated stress display enhanced morphine analgesia. This study examined the possible contribution of classically conditioned analgesia to this effect. First, drug-naive rats exposed to nine daily sessions of stress, each consisting of a single 45-s exposure to footshock, subsequently displayed enhanced analgesic responsiveness to morphine 1 and 10 days after stress (Experiments 1, 2, and 5). This enhancement was also observed in morphine-experienced rats 1 and 8 days after stress (Experiment 1). Second, the effect of footshock stress on morphine analgesia was found to be specific to the environment in which stress was administered (Experiments 2 and 3). Rats tested in the same distinctive environment in which stress was administered displayed enhanced morphine analgesia; rats shocked elsewhere did not differ from nonshocked controls (Experiment 2). Third, conditioned analgesia was found under the same conditions that yielded enhanced morphine analgesia (Experiments 2 and 4). Lastly, both this conditioned analgesia and the acute analgesia elicited by the footshock stressor were found to be attenuated by naloxone (Experiments 5 and 6). These data are consistent with the hypothesis that the enhanced morphine analgesia observed after repeated footshock stress reflects the contribution of an opioid mediated , conditioned analgesia elicited by cues formerly paired with the stressor.

Evidence for the independence of brainstem mechanisms mediating analgesia induced by morphine and two forms of stress

Exposure to inescapable footshock stress causes potent analgesia in the rat. According to several criteria, prolonged, intermittent footshock elicits analgesia mediated by opioid peptides, whereas brief, continuous footshock produces non-opioid analgesia. We now report that these neurochemically discrete forms of stress analgesia also have different neuroanatomical bases. Electrolytic lesions damaging greater than 85% of the n. raphe magnus (complete NRM lesions), but not lesions of the same size causing less NRM damage (partial NRM lesions) significantly reduce only the non-opioid form of stress analgesia. In the same animals, complete and partial NRM lesions disrupt morphine analgesia; however, our analyses indicate that this effect is not mediated by the same substrate involved in either form of stress analgesia. These results support the existence of multiple endogenous analgesia mechanisms and indicate a complex role for the NRM in these systems.

Effects of naloxone and hypophysectomy on electroconvulsive shock-induced analgesia.

Powerful analgesia follows electroconvulsive shock in both hypophysectomized and sham-operated rats. Antagonism of this analgesia by naloxone implicates opioid peptides in its mediation, its occurrence in hypophysectomized animals implicating opioids of central nervous system rather than pituitary origin. Because naloxone only partially reduces electroconvulsive shock analgesia in hypophysectomized rats, the participation of another, non-opioid analgesia substrate also seems indicated.

The preferential release of beta-endorphin from the anterior pituitary lobe by Corticotropin Releasing Factor (CRF)

Although a number of investigators have shown that release of ACTH is accompanied by the release of Beta-endorphin (beta-End) and Beta-lipotropin (beta-LPH), the proportion of the latter two peptides released with stress or by CRF is unclear. To evaluate directly the release of beta-End versus beta-LPH from the anterior lobe, we used molecular sieving of plasma and subsequent radioimmunoassay to measure release of both beta-End and beta-LPH into plasma after thirty minutes of inescapable intermittent footshock. We found a substantial increase in circulating beta-End which appears to be of anterior lobe origin. The beta-End does not appear to represent peripheral conversion of beta-LPH to beta-End since the ratio of beta-LPH:beta-End released remained constant between five and thirty minutes of stress, and the rate of disappearance of beta-LPH is slower than the rate of disappearance of beta-End following the termination of stress. Further confirmation of these findings was obtained by examining the POMC derived peptides released by pituitary cell suspensions in the presence and absence of oCRF. While unstimulated release consisted of equal proportions of beta-End and beta-LPH, stimulation of the anterior lobe cell suspensions with oCRF resulted in the release of two-fold more beta-End than beta-LPH.