Cross tolerance between morphine and the long-term analgesic reaction to inescapable shock

doi:10.1016/0091-3057(81)90130-1

Pharmacology Biochemistry and Behavior

Volume 14, Issue 5, May 1981, Pages 677-682

https://doi.org/10.1016/0091-3057(81)90130-1 Get rights and content

Abstract

Animals exposed to a variety of stressors display a temporary analgesic reaction. This short-term analgesic has been shown to be reversible by opiate antagonists and cross-tolerant with morphine following some stress conditions, but not following others. It has recently been shown that inescapable shock parameters which produce behavioral “learned helplessness” effects also produce a short-term analgesic reaction, and that this reaction can be re-aroused by a brief exposure to shock 24 hours later. Further, both the immediate and long-term antinociceptive reaction which follow shocks of this type have been shown to be reversible by opiate antagonists. Here it is shown that the long-term analgesic reaction is completely cross tolerant with morphine. Implications of these results for opioid mediation of learned helplessness and opioid versus nonopioid mediation of stress-induced analgesia are discussed.

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Cited by (62)

Review of neuroimaging studies related to pain modulation
2011, Scandinavian Journal of Pain
Citation Excerpt :
The intensity, duration and type of stressor may determine the type of SIA as well as the degree of the subsequent analgesia. The sequential exposure of rats to a series of inescapable foot shocks, for instance, resulted in both an early naltrexone-insensitive and a late naltrexone-sensitive analgesia [153]. Naltrexone is an opioid receptor antagonist [154].
A noxious stimulus does not necessarily cause pain. Nociceptive signals arising from a noxious stimulus are subject to modulation via endogenous inhibitory and facilitatory mechanisms as they travel from the periphery to the dorsal horn or brainstem and on to higher brain sites. Research on the neural structures underlying endogenous pain modulation has largely been restricted to animal research due to the invasiveness of such studies (e.g., spinal cord transection, brain lesioning, brain site stimulation). Neuroimaging techniques (e.g., magnetoencephalography (MEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)) provide non-invasive means to study neural structures in humans. The aim is to provide a narrative review of neuroimaging studies related to human pain control mechanisms.
The approach taken is to summarise specific pain modulation mechanisms within the somatosensory (diffuse noxious inhibitory controls, acupuncture, movement), affective (depression, anxiety, catastrophizing, stress) and cognitive (anticipation/placebo, attention/distraction, hypnosis) domains with emphasis on the contribution of neuroimaging studies.
Findings from imaging studies are complex reflecting activation or deactivation in numerous brain areas. Despite this, neuroimaging techniques have clarified supraspinal sites involved in a number of pain control mechanisms. The periaqueductal grey (PAG) is one area that has consistently been shown to be activated across the majority of pain mechanisms. Activity in the rostral ventromedial medulla known to relay descending modulation from the PAG, has also been observed both during acupuncture analgesia and anxiety-induced hyperalgesia. Other brain areas that appear to be involved in a number of mechanisms are the anterior cingulate cortex, prefrontal cortex, orbitofrontal cortex and nucleus accumbens, but their exact role is less clear.
Neuroimaging studies have provided essential information about the pain modulatory pathways under normal conditions, but much is still to be determined. Understanding the mechanisms of pain control is important for understanding the mechanisms that contribute to failed pain control in chronic pain. Applying fMRI outside the brain, such as in the trigeminal nucleus caudalis of the spinotrigeminal pathway and in the dorsal horn of the spinal cord, and coupling brain activity with activity at these sites may help improve our understanding of the function of brain sites and shed light on functional connectivity in the pain pathway.
Stress-induced analgesia: Prediction of posttraumatic stress symptoms in battered versus nonbattered women
2002, Biological Psychiatry
Citation Excerpt :
Furthermore, this response shows more reversibility with opiate antagonists (Hyson et al 1982). Finally, only inescapable shock produces an analgesia that can be reinstated 24 hours later with a brief reexposure to shock (Jackson et al 1979), and this reinstated analgesia is found to be completely reversible by opiate antagonists (Maier et al 1980) and cross-tolerant with morphine (Drugan et al 1981). It has been suggested that organisms exposed to an extended series of inescapable shocks might display an initial nonopioid analgesia followed by an opioid form as the organism learns that the shocks are uncontrollable (Drugan et al 1982).
Background: Chronic and inescapable trauma is implicated in the stress-induced analgesia (SIA) response.
Methods: A sample of 27 chronically battered women was compared with 28 trauma-exposed nonbattered women on their SIA response at 1 month postindex assault.
Results: For the battered women sample, the SIA response at 1 month postindex assault was found to significantly predict an increase in posttraumatic stress disorder-related hyperarousal at 3 months postindex assault. Furthermore, the battered women showed a significant increase in depression symptoms from 1 to 3 months postindex assault compared with the nonbattered women, who showed a significant decrease.
Conclusions: The findings suggest that the chronic and inescapable nature of trauma exposure in the battered women might account for an SIA response that is qualitatively different from that seen in the nonbattered women. It is suggested that the mechanism underlying the SIA response in battered women might be opioid mediated and that it might be responsible for the significant prediction of physiologic hyperarousal. Furthermore, this hyperarousal might moderate the relationship between the SIA response and depression.
Behavioral analysis of stress controllability effects in a new swim stress paradigm
2001, Pharmacology Biochemistry and Behavior
Previous animal stress studies have illustrated the marked impact of coping on subsequent behavior and physiology by using shock as the stressor. The current study evaluates the generality of shock stress controllability effects in a new swim stress paradigm on several dependent measures: behavioral despair, analgesia, shuttlebox escape, and alcohol reactivity. In this new paradigm, rats in the escape group are able to learn the behavioral response as evidenced by significant reduction in the acquisition of a lever press response. Both escape and yoked subjects showed “behavioral despair” in comparison to both restrained and home cage controls when tested 24 h later. In the standard shuttlebox escape task 24-h post-stress, no group differences emerged, although a trend for poorer performance in the yoked subjects was evident. No group differences were observed in pain sensitivity after the first or second forced swim exposure. Finally, stress controllability effects were observed in behavioral reactivity to alcohol 2-h post-stress as measured by rotarod performance. This effect is opposite to the previous observations with the tailshock stress controllability paradigm. These results suggest that (1) there are certain similarities, but some fundamental differences between the behavioral endpoints measured following intermittent swim stress in comparison to the well-established effects of the intermittent tailshock stress model and (2) the qualitative nature of a stressor may markedly influence the behavioral and physiological consequences of stress and coping.
Stress-induced analgesia in μ-opioid receptor knockout mice reveals normal function of the δ-opioid receptor system
2000, Brain Research
Citation Excerpt :
However, the action of exogenous ligands may be significantly different from those of endogenous ligands. The endogenous release of opioid ligands is well studied and can be produced using inescapable shock [5,8], social-conflict [26], or forced swim stresses [7,19,32]. Opioid induced analgesia following forced swim is dependent upon the length of swim [32], parameters of swim (i.e. continuous or intermittent) [7], strain and sex of animal [2,15,16,18,20,21], and water temperature [24].
Stress-induced analgesia (SIA) was examined in wildtype and μ-opioid receptor knockout mice. We used thermal paw withdrawal (TPW) latency following a continuous 3-min swim in 20°C water, and found a significant increase in TPW latency in both wild-type and knockout mice. Pre-treatment prior to the swim with naltrindole, a selective δ-opioid receptor antagonist, blocked the increase in TPW latency in knockout mice. These results demonstrate an intact δ-receptor-mediated function of a physiologically-released endogenous agonist in the μ-opioid receptor knockout mouse. The present findings are in contrast with previous reports that analgesia induced by exogenous delta agonists is reduced in the knockout mice.
Activation of serotonin-immunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor
1999, Brain Research
The dorsal raphe nucleus (DRN) and its serotonergic terminal regions have been suggested to be part of the neural substrate by which exposure to uncontrollable stressors produces poor escape responding and enhanced conditioned fear expression. Such stressor exposure is thought to selectively activate DRN serotonergic neurons in such a way as to render them transiently sensitized to further input. As a result of this sensitized state, behavioral testing procedures are thought to cause excess serotonergic activity in brain regions that control these behaviors. The present studies were conducted to investigate activity in the DRN following exposure to escapable and yoked, inescapable tailshock. Neural activity was characterized using immunohistochemistry to detect the immediate early gene product Fos in serotonin-immunoreactive cells in the DRN. Inescapable tailshock led to greater serotonergic neural activity than did escapable tailshock, supporting the hypothesis that uncontrollable stressors preferentially activate serotonergic neurons in the DRN.
Opioid-dependent effects of inescapable shock on escape behavior and conditioned fear responding are mediated by the dorsal raphe nucleus
1999, Behavioural Brain Research
Manipulations of the dorsal raphe nucleus (DRN) modulate the behavioral effects of exposure to inescapable shock (IS). Opiate agonists and antagonists also influence the impact of IS, but the role of the DRN in mediating these effects is unknown. The opiate antagonist naltrexone micro-injected into the region of the DRN immediately prior to IS prevented both the escape deficit and the enhancement of fear conditioning that occur 24 h later. Intra-DRN naltrexone administered at the time of later behavioral testing reduced, but did not eliminate, these effects of prior IS. Conversely, the opiate agonist morphine, in combination with a subthreshold number of 20 IS trials, induced an escape deficit and enhanced conditioned fear 24 h later. Microinjections of naltrexone into the dorsolateral periaqueductal gray area did not alter the effects of IS and electrolytic lesions of the DRN prevented the effect of the morphine-20 IS trial combination. The role of opioids in mediating the behavioral effects of IS is discussed.

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^☆: This research was supported by NSF Grant BNS-78-00508 and RSDA MH 00314 to S. F. Maier, and by a Selected Research Opportunity grant from the ONR, NIDA grant DA 01207, and RSA MH 24161 to J. D. Barchas.

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Cross tolerance between morphine and the long-term analgesic reaction to inescapable shock☆

Abstract

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Psychoneuroendocrinology

Brain Res.

Eur. J. Pharmac.

Neurosci. Biobehav. Rev.

Stress-induced increase in endogenous opiate peptides: Concurrent analgesia and its partial reversal by naloxone

Endogenous opioid ligands may mediate stress-induced changes in the affective properties of pain related behavior in rats

Life Sci.

Enkephalin may mediate euphoria and drive reduction reward

Nature

Stress-induced analgesia: Time course of pain reflex alterations following cold water swims

Bull. Psychonom. Soc.

A perceptual-defensive-recuperative model of fear and pain

Behav. Brain Sci.

Lack of cross-tolerance between morphine and autoanalgesia

Pharmac. Biochem. Behav.