Richard J. Bodnar

Stress-induced analgesia: Neural and hormonal determinants ☆

Extensive evidence has indicated that distinct neural systems specifically designed to inhibit sensitivity to painful stimuli exist. Recent advances suggest that the endorphins, enkephalins and the opiate receptor interact with a descending serotonergic bulbospinal system to mediate the analgesic responses to opiates and electrical stimulation. In assessing the evolutionary and behavioral significance of this pain-inhibitory system, several laboratories discovered that acute exposure to a wide variety of stressful events results in a transient analgesia. Chronic exposure to a number of these stressors results in adaptation of the analgesic response. The purpose of this review is to identify and characterize the mechanisms by which these stressors activate pain-inhibition. The relationship of stress-induced analgesia to each of the following is reviewed: (a) the role of endorphins, enkephalins and the opiate receptor; (b) the role of the descending serotonergic bulbospinal system; (c) the role of the pituitary gland; and (d) the role of hypothalamic mechanisms. Data will be discussed in terms of opiate and non-opiate pain-inhibitory mechanisms, in which some stressors act through the former and other stressors act through the latter.

Stress-produced analgesia and morphine-produced analgesia: Lack of cross-tolerance

Animals exposed to cold-water swims, rotation, inescapable shocks, abrupt food deprivation and other stressors display temporary analgesia. Since repeated exposures result in adaptation of this analgesia in much the same way that repeated administration of opiates results in tolerance, the possibility of cross-tolerance between cold-water stress-induced and morphine-induced analgesia was investigated. Flinch-jump thresholds were determined in ten experimental groups of six rats each. Three groups showed dose-dependent analgesia following single injections of morphine at 5, 10 and 15 mg/kg, respectively. A fourth group, subjected to a single cold-water swim at 2 degrees C for 3.5 min, displayed analgesia comparable to that produced by 10 mg/kg of morphine. Groups subjected either to 14 daily cold-water swims or to 14 daily morphine injections at 10 mg/kg showed normal thresholds on the 14th day indicating that adaptation and tolerance had developed, respectively. The cross-over groups were exposed to either 13 days of could-water swims followed by morphine or the reverse arrangement. Both groups showed profound analgesia instead of cross-tolerance, suggesting that a non-opiate neural mechanism may mediate stress-induced analgesia.

Analgesia induced by cold-water stress: Attenuation following hypophysectomy.

In addition to the well-known activation of the pituitary-adrenal axis, acute exposure to severe stressors includes a temporary analgesia in rats. Thus, the present study investigates whether the pituitary was involved in the mediation of analgesia induced by severe cold-water swim (CWS) stress. Flinch-jump thresholds were measured 30 min following 3.5-min swims in water temperatures ranging from 2-35 degrees C. Compared with untreated normal rats, hypophysectomized rats, receiving corticosterone and thyroxin, displayed significantly less CWS-induced analgesia, while similarly-supplemented normal rats exhibited significantly more CWS-induced analgesia. In a second experiment, operant liminal escape pain thresholds were determined following acute and chronic CWS. Whereas normal rats exhibited profound analgesia following the initial swims, the hypophysectomized rats never displayed any CWS-induced operant escape shifts. Stress-induced alterations in general activity levels and/or thermoregulation were shown to be unrelated to the diminished effectiveness of CNS to produce analgesia in hypophysectomized rats. These data imply that the pituitary is involved in the mediation of CWS-induced analgesia.

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

Recent reports indicate that rats acutely stressed by inescapable footshock, rotation, restraint, or injections of hypertonic saline display increased tail-flick latencies. The present study parametrically analyzed the time course of analgesia following exposure to another stressor, a brief, forced cold water swim, by means of three nociceptive reflex tests. Rats acutely subjected to a cold water (2°C) swim for 3.5 min displayed significantly elevated tail-pinch and flinch-jump thresholds for up to 60 min; no change was noted in similarly treated warm water (28°C) controls. Tail-flick withdrawal latencies to radiant heat stimuli exhibited similar, but more enduring, increases, lasting up to 120 min. These results demonstrate that reactivity to three different nociceptive reflex modalities, electric shock, heat, and pressure, can be altered by acute exposure to a stressor.

Opiate and non-opiate mechanisms of stress-induced analgesia: Cross-tolerance between stressors

Abstract Acute exposure to severe stressors induce profound analgesia. Repeated exposures to the same stressors esult in adaptation in much the same way that repeated administration of opiates results in tolerance. The present study investigated whether two qualitatively different stressors, cold-water swims (CWS) and injections of 2-deoxy-D-glucose (2-DG) share common pain-inhibitory mechanisms by determining whether cross-tolerance developed to their analgesic effects. Cross-tolerance was also examined between 2-DG and morphine. Flinch-jump thresholds were determined in six groups of six rats each. Analgesia was observed 30 min following acute exposure to CWS (2°C for 3.5 min), 2-DG (350 mg/kg) and morphine (10 mg/kg), but not following placebo injections or warm water swims. Chronic exposure to all three analgesic treatments resulted in tolerance and adaptation. Complete and reciprocal cross-tolerance developed between the analgesia induced by CWS and by DG. Complete cross-tolerance to 2-DG analgesia also developed in morphine-tolerant rats, but only partial cross-tolerance to morphine analgesia developed in 2-DG adapted rats. These results support the concept that stressful events induce analgesia through specific activation of an intrinsic pain-inhibitory system which has both opiate and non-opiate branches.

Neuropharmacological and Neuroendocrine Substrates of Stress-Induced Analgesia

The ability of a number of stressful and other environmental stimuli to elicit a transient analgesic response following acute exposure is well established and serves as a useful, noninvasive means for activating intrinsic pain-inhibitory pathways. However, given the diversity in the profiles of the analgesic responses induced by such stimuli?-4 it appears that multiple pain-inhibitory systems exist. Two major dimensions by which analgesic stressors have been categorized are whether they are mediated by the endogenous opioids or by purely neural or neurohormonal mechanisms.) The physiological mechanisms subserving inescapable footshock analgesia are covered in other chapters of this volume; this chapter will focus on the physiological profiles of two other analgesic environmental stressors studied extensively by our laboratory: cold-water swims (CWS) and 2-deoxy-~-g~ucose (2DG) glucoprivation. Both stimuli produce increases in pituitary-adrenal stress responses, and also have the advantage of eliciting other measurable physiological responses in addition to analgesia. Therefore, by analyzing the analgesic and hypothermic responses following CWS, and the analgesic and hyperphagic responses following 2DG, one can determine whether a given manipulation is affecting analgesic pain-inhibitory systems selectively, or rather changing multiple responses to a stressor. The issues that will be reviewed are opiate involvement, neuroendocrine involvement, hypothalamic involvement, neuropharmacological profiles, and an interactive model of opiate and nonopiate pain-inhibitory systems.

Central opioid receptor subtype antagonists differentially alter sucrose and deprivation-induced water intake in rats

The present study compared the effectiveness of centrally-administered opioid receptor subtype antagonists to inhibit intake of either a 10% sucrose solution under ad libitum conditions, or water following 24 h of water deprivation. Full dose-response functions were evaluated over a 1 h period for the following antagonists: naltrexone (general: 1-50 micrograms), nor-binaltorphamine (Nor-BNI, kappa: 1-20 micrograms), beta-funaltrexamine (beta-FNA, mu: 1-20 micrograms), naltrindole (delta 2: 1-20 micrograms), [D-Ala2, Leu5, Cys6]-enkephalin (DALCE, delta 1: 10-40 micrograms) and naloxonazine (mu 1: 10-50 micrograms). Naltrexone significantly and dose-dependently inhibited both sucrose intake (64-67%) and deprivation-induced water intake (53-67%). Nor-BNI significantly and dose-dependently inhibited sucrose intake (53-55%), but failed to significantly affect (28%) deprivation-induced water intake. beta-FNA significantly and dose-dependently inhibited both sucrose intake (31-34%) and deprivation-induced water intake (36-50%). Naltrindole failed to significantly alter either sucrose intake (24%) or deprivation-induced water intake (16%). Whereas DALCE significantly, but transiently (15-20 min) inhibited sucrose intake (28%), it failed to significantly alter deprivation-induced water intake (14%). Naloxonazine significantly, but transiently (5-10 min) stimulated sucrose intake at low doses (26%), but non-significantly reduced sucrose intake at higher doses (20%). Naloxonazine failed to significantly alter deprivation-induced water intake (16% reduction). These data indicate that whereas the kappa and mu 2 binding sites participate in the opioid modulation of sucrose intake, the mu 2 binding site participates in the opioid modulation of deprivation-induced water intake.

Involvement of opioid receptor subtypes in rat feeding behavior

The short-acting opiate antagonist naloxone decreases food intake in three models of ingestive behavior: free feeding, food-deprivation induced feeding and deoxyglucose-induced feeding. Twenty-four hours after administration, the long-acting, mu1 selective antagonist naloxonazine inhibits food intake to the same extent as naloxone in freely feeding and food-deprived rats, but not in animals treated with 2-deoxyglucose. These results indicate that 1) opiates modulate feeding through multiple opioid receptor mechanisms, one of which is the mu subtype, and 2) the feeding observed in various experimental paradigms are modulated by different receptor subtypes. Furthermore, these results illustrate the usefulness of naloxone in defining a behavior as opioid but point out its limitations in discriminating between opioid receptor subtypes.

Naloxazone and pain-inhibitory systems: evidence for a collateral inhibition model

The analgesic responses following morphine and cold-water swims (CWS) can be dissociated from each other. Indeed, certain manipulations in rats such as hypophysectomy or D-phenylalanine injections decrease CWS analgesia while increasing morphine analgesia. The present study examined the reciprocal notion, namely whether a manipulation that decreases morphine analgesia would increase CWS analgesia. Naloxazone, an opiate antagonist which selectively inhibits the high affinity binding site in a long-acting manner, was administered intracerebroventricularly and assessed for its effects upon morphine analgesia and CWS analgesia as measured by the jump test. While intracerebroventricular injections of naloxazone reduced morphine analgesia at 0.5 and 24 hr following microinjection, the same 50 micrograms dose significantly increased CWS analgesia at 0.5 hr after injection, suggesting a mechanism of collateral inhibition between opioid and non-opioid pain-inhibitory systems.

Central opioid receptor subtype antagonists differentially reduce intake of saccharin and maltose dextrin solutions in rats

Opioid modulation of ingestion includes general opioid antagonism of deprivation-induced water intake and intake of sucrose and saccharin solutions. Previous studies using selective subtype antagonists indicated that opioid effects upon deprivation-induced water intake occurred through the mu2 receptor and that opioid effects upon sucrose intake occurred through kappa and mu2 receptors. The present study compared the effects of intracerebroventricular administration of opioid receptor subtype antagonists upon intakes of a saccharin solution and a maltose dextrin (MD) solution to determine which receptor subtypes were involved in modulation of ingestion of different preferred tastants. Significant reductions in saccharin intake (1 h) occurred following naltrexone (20-50 micrograms: 66%) and naltrindole (delta, 20 micrograms: 75%), whereas [D-Ala2, Leu5, Cys6]-enkephalin (DALCE, delta 1, 40 micrograms: 45%) had transient (5 min) effects. Neither beta-funaltrexamine (B-FNA, mu), naloxonazine (mu1), nor nor-binaltorphamine (Nor-BNI, kappa) significantly altered saccharin intake. Significant reductions in MD intake (1 h) occurred following naltrexone (5-50 micrograms: 69%) and B-FNA (1-20 micrograms: 38%). MD intake was not reduced by naltrindole, DALCE, naloxonazine and Nor-BNI. Peak antagonist effects were delayed (20-25 min) to reflect interference with the maintenance, rather than the initiation of saccharin or MD intake. Comparisons of opioid antagonist effects across intake situations revealed that naltrexone had consistently low ID40 values for saccharin (29 nmol), MD (25 nmol), sucrose (6 nmol) and deprivation (38 nmol) intake. Despite its significant effects relative to naloxonazine, B-FNA had significantly higher ID40 values for saccharin (800 nmol), MD (763 nmol) and sucrose (508 nmol) relative to deprivation (99 nmol) intake, suggesting that mu2 receptors may be mediating maintenance of intake rather than taste effects. Nor-BNI had low ID40 values for intake of sucrose (4 nmol), but not for saccharin (168 nmol), MD (153 nmol) and deprivation (176 nmol), suggesting that kappa receptors may mediate ingestion of sweet-tasting stimuli. That delta (naltrindole: ID40 = 60 nmol), but not delta 1 (DALCE: ID40 = 288 nmol) antagonists consistently reduce saccharin intake suggests a role for the delta 2 receptor subtype in the modulation of hedonic orosensory signals.