Opiate vs non-opiate footshock-induced analgesia (FSIA): The body region shocked is a critical factor

Previous work has demonstrated that footshock can elicit either opiate or non-opiate analgesia. The present study has demonstrated that one critical factor determining the involvement of endogenous opioids is the body region shocked. Using 90 s shock, front paw shock produced an opiate analgesia which was significantly antagonized by as little as 0.1 mg/kg systemic naloxone and morphine tolerance. In the latter experiment, a parallel recovery of the analgesic potencies of both front paw shock and morphine was observed following 2 weeks of opiate abstinence. In contrast, hind paw shock produced a non-opiate analgesia which failed to be attenuated by 20 mg/kg systemic naloxone and showed no cross-tolerance to morphine. Since identical shock parameters were used for front paw and hind paw shock in the systemic naloxone experiments, stress per se clearly cannot be the crucial factor determining the involvement of endogenous opioids in footshock-induced analgesia. These results were discussed with respect to clinical treatments of pain which utilize somatosensory stimulation.     

Classical conditioning of front paw and hind paw footshock induced analgesia (FSIA): Naloxone reversibility and descending pathways

Opiate and non-opiate footshock induced analgesia (FSIA) can be differentially elicited dependent upon the body region shocked. As measured by the spinally-mediated tail flick test, hind paw shock produces non-opiate analgesia whereas front paw shock produces opiate analgesia. The present series of experiments utilized cord lesions and transections to identify descending and intraspinal pathways mediating front paw and hind paw FSIA. The results of these studies indicate that front paw shock leads to activation of supraspinal sites which mediate analgeshi via descending pathways lying solely within the dorsolateral funiculus (DLF) of the spinal cord; direct intraspinal pathways are not involved. Hind paw FSIA is also mediated by a descending DLF pathway but is unlike front paw FSIA in that it involves intraspinal pathways as well. This work provides further parallels between the analgesias produced by morphine, electrical brain stimulation and environmental stimuli.     

The neural basis of footshock analgesia: The role of specific ventral medullary nuclei

Previous studies have demonstrated that brief front paw shock produces opiate analgesia while brief hind paw shock produces non-opiate analgesia in rats. Additionally, front paw shock and hind paw shock can produce an opiate-mediated classically conditioned analgesia; that is, when shock is delivered to an animal, environmental cues become associated with this stimulus such that these cues become capable of producing potent opiate analgesia in the absence of shock. Investigations of the neural bases of these phenomena have revealed that front paw shock and classical conditioning lead to activation of supraspinal sites which mediate analgesia via descending pathways lying solely within the dorsolateral funiculus (DLF) of the spinal cord. Hind paw footshock induced analgesia (FSIA) is also mediated by a descending DLF pathway but is unlike front paw FSIA or classically conditioned analgesia in that it involves intraspinal pathways as well. The aim of the present series of experiments was to identify the supraspinal origin of the centrifugal DLF pathway mediating front paw (opiate) FSIA, hind paw (non-opiate) FSIA, and classically conditioned (opiate) analgesia. These studies examined the effect of electrolytic lesions of the nucleus raraphe magnus (NRM), nucleus reticularis paragigantocellularis (PGC), and combined lesions of these two areas (nucleus raphe alatus, NRA) on these environmentally-induced analgesias. The results of this work indicate that the NRA is the origin of the spinal cord DLF pathway mediating front paw (opiate) FSIA and classically conditioned (opiate) analgesia. Hind paw (non-opiate) FSIA is also mediated, in part, by the NRA but must involve another, yet unidentified, brainstem site(s) as well.     

The neurochemical basis of footshock analgesia: the role of spinal cord serotonin and norepinephrine

Previous studies have demonstrated that brief front paw and brief hind paw shock produce potent opiate and non-opiate analgesia, respectively. Additionally, opiate analgesia can be classically conditioned by using either front paw shock or hind paw shock as the unconditioned stimulus. Front paw footshock-induced analgesia (FSIA), hind paw FSIA, and classically conditioned analgesia are similar in that each is mediated by a medullospinal pathway. However, the neurochemistry of these medullospinal connections has never been investigated. One question which arises is whether any of these phenomena are mediated by monoaminergic neurotransmitters at the level of the spinal cord. The present series of experiments examined the effect of depleting spinal serotonin (5-HT) and combined depletion of spinal 5-HT and norepinephrine (NE) on front paw FSIA, hind paw FSIA, and classically conditioned analgesia. Hind paw FSIA and classically conditioned analgesia were not attenuated by either of these neurochemical manipulations. Front paw FSIA was significantly reduced by both 5-HT depletion and combined 5-HT and NE depletion. To assess the relative importance of spinal 5 HT and NE in front paw FSIA, NE and 5-HT antagonists were injected onto the lumbosacral cord prior to shock exposure. Attenuation of front paw FSIA by equimolar doses of the monoamine blockers was much greater following injection of the 5-HT blocker than after the NE blocker. These data indicate that spinal 5-HT and, apparently to a lesser extent, spinal NE mediate front paw (opiate) FSIA whereas neither 5-HT nor NE appears to mediate hind paw FSIA or classically conditioned analgesia.     

Footshock induced analgesia in dependent neither on pituitary nor sympathetic activation

A variety of environmental stimuli have been demonstrated to produce potent behavioral analgesia. Of these, footshock has been shown to be capable of differentially eliciting opiate or non-opiate analgesia dependent upon the body region shocked; front paw and hind paw shock produce opiate and non-opiate analgesia, respectively. In addition, footshock can be used as a conditioned stimulus to elicit classically conditioned opiate analgesia. A question which arises is whether such pain inhibition is mediated by neural or hormonal pathways. Evidence exists which suggests that endogenous opioids in the pituitary and adrenal medulla may be involved in the production of environmentally induced analgesia. Furthermore, epinephrine administration has previously been shown to produce pronounced pain inhibition. However, the present series of experiments demonstrate that the pituitary-adrenal cortical and sympathetic-adrenal medullary axes are neither necessary nor sufficient for the production of footshock induced analgesia (FSIA). Hypophysectomy failed to attenuate front paw FSIA, hind paw FSIA or classically conditioned analgesia indicating that pituitary β-endorphin or other pituitary factors are not necessary for the production of analgesia. Adrenal opioids and peripheral catecholamines are also not critical since front paw FSIA was potentiated by adrenalectomy or total sympathetic blockade. Furthermore, pituitary and sympathetic activation are not sufficient for the production of analgesia since low thoracic spinalization allows normal hormonal response to front paw shock yet abolishes shock-induced inhibition of the spinally mediated tail flick reflex. These results provide strong evidence that front paw FSIA, hind paw FSIA and classically conditioned analgesia are mediated by neural, rather than hormonal, pathways and provide further parallels between these forms of environmental analgesia, morphine analgesia and brain stimulation produced analgesia.     

The neural basis of footshock analgesia: The effect of periaqueductal gray lesions and decerebration

Previous studies have demonstrated that brief front paw shock and brief hind paw shock produce potent opiate and non-opiate analgesia, respectively. Front paw footshock-induced analgesia (FSIA) and hind paw FSIA are similar in that each is mediated by a medullospinal pathway. A question which arises is whether these opiate and non-opiate descending pathways are activated in direct response to afferent information from the spinal cord or whether indirect activation via more rostral centers is required. The first experiment examined the effect of lesions of the rostral periaqueductal gray (PAG) and caudal PAG on front paw (opiate) FSIA and hind paw (non-opiate) FSIA. In no case did PAG lesions markedly reduce the magnitude of these pain inhibitory states. Since this result raised the possibility that rostral centers may not have any major involvement in the production of these phenomena, the second experiment examined the effect of decerebration on front paw FSIA and hind paw FSIA. Decerebration had no effect on hind paw FSIA and, at most, produced only a very modest decrease in front paw FSIA. The fact that potent and prolonged analgesia can still be elicited after decerebration clearly demonstrates that limbic, cortical, thalamic, and rostral midbrain structures are not critical to the production of these pain inhibitory effects. Thus this work provides the first demonstration of opiate and non-opiate analgesia systems within the caudal brainstem and spinal cord which can be activated by environmental stimuli.     

Muscarinic cholinergic mediation of opiate and non-opiate environmentally induced analgesias

Previous studies have demonstrated that brief front paw shock and brief hind paw shock produce prolonged opiate and non-opiate analgesia, respectively. Additionally, opiate analgesia can be classically conditioned by using either front paw shock or hind paw shock as the unconditioned stimulus. However, beyond this point little is known regarding the neurochemistry of these phenomena. The present series of studies examined the potential involvement of nicotinic and muscarinic cholinergic systems in these 3 forms of environmentally induced analgesia. These experiments demonstrate that muscarinic cholinergic sites within the central nervous system are critically involved in the mediation of both hind paw (non-opiate) foot shock-induced analgesia (FSIA) and classically conditioned (opiate) analgesia since scopolamine, but not equimolar methylscopolamine, significantly attenuated analgesia. Furthermore, the primary muscarine site(s) appears to exist at a supraspinal, rather than spinal, level since delivery of scopolamine directly to the lumbosacral cord produced, at most, only a slight decrease in analgesia. Nicotinic systems do not appear to be importantly involved in any of these forms of environmentally induced analgesias since mecamylamine had no effect on either front paw FSIA or hind paw FSIA and, at most, produced only a slight reduction in classically conditioned analgesia. These data and a review of the literature suggest that the critical cholinergic sites involved in hind paw FSIA exist within the caudal brainstem whereas cholinergic sites within more rostral brain levels probably mediate classically conditioned analgesia.     

Body region shocked need not critically define the neurochemical basis of stress analgesia

Both opioid and non-opioid forms of stress-induced analgesia have been demonstrated in rats, although the conditions leading to their selective activation are still being investigated. We have shown that variations in shock intensity, duration or temporal pattern can determine whether opioid or non-opioid stress analgesia occurs. Others have suggested that body region shocked is the critical determinant, analgesia from front paw shock being opioid and that from hind paw shock non-opioid. We now report that either opioid or non-opioid stress analgesia can be evoked from either front or hind paws depending only on footshock intensity when duration and temporal pattern are held constant.     

Cholecystokinin antagonists selectively potentiate analgesia induced by endogenous opiates

We have recently observed that exogenous sulfated cholecystokinin octapeptide (CCK) can antagonize various forms of opiate analgesia and that the CCK receptor blocker proglumide potentiates morphine analgesia. These observations, plus the similarity in the distribution of CCK and opiate systems, suggest that endogenous CCK may act as a physiological opiate antagonist. We have extended these initial studies by examining the effect of CCK antagonists on opiate analgesia produced by release of endogenous opiates (front paw footshock induced analgesia) and by intrathecal administration of D-Ala-methionine enkephalinamide, a stable analogue of an endogenous opiate. Additionally, the specificity of proglumide's effect was examined by testing the effect of this drug on various forms of non-opiate analgesia. This series of experiments demonstrate that CCK antagonists can markedly potentiate analgesia induced by endogenous opiates and provide strong support for the hypothesis that endogenous CCK systems can oppose the analgesic effects of opiates. Potentiation of analgesia by CCK receptor blockers appears to be selective for opiate systems since proglumide typically attenuated or had no effect on various forms of non-opiate analgesia. These data suggest that CCK blockers may be clinically useful for enhancing the analgesic effects of procedures such as acupuncture, which may be mediated by release of endogenous opiates.     

Opposing actions of cimetidine on naloxone-sensitive and naloxone-insensitive forms of footshock-induced analgesia

The effects of the opiate antagonist naloxone (10 mg/kg) and the histamine H₂-antagonist cimetidine (100 mg/kg; both administered i.p.) were studied on the analgesia elicited by 3 currents of continuous-scrambled AC footshock (FSIA). Repeated analgesic measurements were made in each animal by use of the radiant heat tail-flick test. As shown by others, naloxone effectively inhibited the FSIA produced by 3 min of 2.0 mA, but had no effect on the responses elicited by higher currents (2.5 and 3.5 mA) of the same duration. Cimetidine significantly reduced the naloxone-insensitive FSIA after 3.5 mA, had no effect on that produced by 2.5 mA andpotentiated the naloxone-sensitive analgesia elicited by 2.0 mA. These findings add to existing data supporting a role for brain histamine as a mediator of naloxone-insensitive analgesia, and also suggest the possibility that histamine may mediate hyperalgesic responses.     

Different opioid systems may participate in post-electro-convulsive shock (ECS) analgesia and catalepsy

Administration of electroconvulsive shock (ECS) to rats results in post-ictal analgesia and catalepsy both of which can be partially reversed by the opiate antagonists, naloxone and naltrexone. Tolerance to both phenomena develops following daily ECS administrations for 10 days. However, qualitatively different patterns of tolerance development of analgesia and catalepsy are seen. Naloxone treatment prior to ECS provides partial protection against the development of tolerance to ECS-induced catalepsy but does not prevent the tolerance to post-ECS analgesia. In contrast, the long-lasting opiate antagonist, naltrexone, blocked the development of tolerance to ECS analgesia. Furthermore, the same animals that showed tolerance to the analgesic effects of repeated ECS failed to show analgesia following the administration of 10 mg/kg of morphine while naltrexone, but not naloxone, treatment prior to ECS blocked the development of cross-tolerance to morphine analgesia. A dose-response investigation of morphine's action (5, 10, 15 and 20 mg/kg) in additional animals receiving 10 daily administrations of ECS reveals that a greater tolerance to morphine's motor inhibitory effect than to its analgesic effect results from repeated ECS administration. Finally, animals receiving daily injections of either a low (10 mg/kg) or a high (100 mg/kg) dose of morphine for 10 days showed markedly attenuated post-ECS analgesia and catalepsy. However, whereas similar effects of opiate antagonists and the chronic administration of both doses of morphine were observed with post-ECS catalepsy, analgesia was least affected by naloxone (50% of control) and most affected by the chronic high dose of morphine (14% of control). Furthermore, a similar degree of tolerance to post-ECS analgesia was seen following either repeated ECS in drug-naive animals or the chronic administration of the high dose of morphine. Thus, the partial naloxone blockade of ECS analgesia and the more substantial attenuation of post-ECS analgesia seen in morphine-tolerant animals provide different estimates of opioid involvement in these phenomena. It is proposed that these results may demonstrate the involvement of different opioid systems in analgesia and catalepsy and it is suggested that more than one opioid system may also be involved in post-ECS analgesia.     

Opiate and non-opiate analgesia induced by inescapable tail-shock: Effects of dorsolateral funiculus lesions and decerebration

Previous studies have demonstrated that inescapable tail-shock can produce either non-opiate or opiate short-term analgesia, dependent on the number of shocks delivered. Additionally, extended exposure to inescapable tail shock can produce long-term, opiate analgesic effects. Several lines of investigation suggest that the psychological dimension of perceived controllability may powerfully influence these phenomena in that each form of opiate analgesia can only be produced following exposure to inescapable, rather than equal amounts and distribution of escapable, shock. This has suggested that these opiate analgesias result from the organism's learning that it has no control over shock. Although it has been assumed that the opiate and non-opiate analgesias induced by tail shock may be subserved by neural circuitry similar to that mediating morphine analgesia and other forms of environmentally induced analgesia, no direct evidence exists to support this assumption. The present study sought to provide an initial attempt at defining the neural circuitry involved in these phenomena by examining the effect of bilateral dorsolateral funiculus (DLF) lesions and decerebration. These experiments revealed that pathways within the spinal cord DLF are critical for the production of short-term non-opiate analgesia, short-term opiate analgesia, and long-term opiate analgesia since bilateral DLF lesions abolished all three pain inhibitory effects. Additionally, it was found that decerebration did not attenuate either the short-term non-opiate or short-term opiate analgesia induced by inescapable tail shock. Combining the observations that these non-opiate and opiate short-term effects are not reduced by decerebration yet are abolished by DLF lesions clearly delimits the source of descending pain inhibition as being within the caudal brainstem.     

Stress induced analgesia: its opioid nature depends on the strain of rat but not on the mode of induction

Reports by several investigators have shown that both opioid and non-opioid analgesia can be induced by non-pharmacological manipulations such as the administration of electric shock, and that such analgesia depends on shock parameters, the affective state of the animal and the region of the body shocked. We tested several manipulations which have been reported to induce opioid analgesia using a local strain of rats (CR). Such manipulations included the used of 30 min of intermittent footshock (3 mA, 1 s on, 5 s off), brief shock to the forepaws, transpinal electroconvulsive shock (ECS) and tail shock induced helplessness. Administration of either naloxone or naltrexone to rats of the CR strain failed to attenuate the analgesic effect of these manipulations and in some cases even enhanced analgesia. The existence of functional opioid analgesia systems in CR rats was evident from the fact that electrical stimulation of the periaqueductal gray area produced naloxone sensitive analgesia. In additional experiments we compared the analgesic effect of brief continuous (3 min) footshock, prolonged intermittent footshock (30 min) and ECS in young (less than 75 days of age) and old (greater than 75 days of age) rats of the Sabra strain. Young Sabra rats showed naloxone sensitive analgesia following all 3 manipulations while adult rats displayed analgesia which was naloxone insensitive. Furthermore, no decrement in learning, indicative of helplessness, could be demonstrated in young Sabras following 3 min of shock which induced naloxone sensitive analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spinal mechanisms of te analgesic action of electroconvulsive shock

The present study investigated the spinal systems involved in the analgesic action of electroconvulsive shock (ECS). To identify such systems complete spinal transections and discrete lesions within the dorsal half of the spinal cord were performed. Complete spinal transection eliminated ECS analgesia totally, demonstrating that the observed analgesic effect is attributable to neural conduction. Lesions within the region of the dorsolateral funiculus (DLF) caused a pronounced, but incomplete, attenuation of ECS analgesia. Larger lesions of the dorsal aspects of the spinal cord including both the DLF and the dorsal column area did not result in further attenuation of analgesia. Thus, it appears that within the dorsal cord the area of the DLF contains the fibers mediating the antinociceptive action of ECS. Additional experiments were conducted to determine the neuromediators involved in ECS analgesia. Of a wide range of antagonists injected intraperitoneally (methysergide, phentolamine, haloperidol, diphenhydramine, naloxone, picrotoxin, theophylline and scopolamine), only methysergide produced a significant attenuation of ECS analgesia. In contrast, following intrathecal injections of antagonists a dose-related decrease of analgesia could be seen after the injection of methysergide, phentolamine and naloxone implicating spinal serotonin, noradrenaline and the enkephalins in the analgesic action of ECS. To assess further the interaction between the action of these neurotransmitter systems, we evaluated the effect of drug pair combinations on ECS analgesia. Intrathecal phentolamine + naloxone, methysergide + naloxone and methysergide + phentolamine were injected at doses that caused maximal attenuation of analgesia. Injections of drug combinations did not result in further attenuation of ECS analgesia. It appears that the analgesic action of ECS is mediated via systems descending within the spinal cord. The main contribution to the analgesic action of ECS is from fibers coursing within the DLF, although contribution of neural systems within the ventral spinal cord also exists. These descending analgesia systems appear to utilize serotonin, noradrenaline and endogenous opioids as neurotransmitters. Additional systems the pharmacological nature of which is still undetermined also exist.     

Opioid-neurotransmitter interactions: Significance in analgesia, tolerance and dependence

1. Opioid analgesics influence the function of a number of neurotransmitter systems including classical neurotransmitters, neuropeptides and endogenous opioids. The role of these interactions in analgesia, tolerance and dependence is reviewed.

2. Opioids inhibit the release of substance P from high threshold primary afferents, depress the activity of dorsal horn neurons and increase activity in serotonergic and noradrenergic neurons projecting from brainstem to spinal regions.

3. Chronic administration of opioids modifies the dynamics of classical transmitters and those of endogenous opioid peptides in the brain, spinal cord and the pituitary gland. However, the effects observed are very variable.

4. Several neuropeptides (vasopressin, MIF, -MSH, CCK and dynorphin) have been reported to modify acute and chronic effects of opioids. Tolerance and dependence seen after opiate administration may involve changes in the function of these peptides.     

Behavioral and physiological studies of non-narcotic analgesia in the rat elicited by certain environmental stimuli

These experiments characterized the analgesia resulting from exposure to certain noxious and/or stressful manipulations. Rats exposed either to electric grid shock (0.35-2.0 mA for 10-30 sec) or to 5 min of presumably non-painful centrifugal rotation (about 7.0 transverse g's) were analgesic as measured by tail-flick, hot plate and responses to applications of a calibrated paw pinch or alligator clip. Analgesia produced by shock (SA) or centrifugal rotation (RA) persisted after termination of these manipulations. Neither SA nor RA were attended by generalized sensory, attentional or motoric deficits. Intraperitoneal injection of hypertonic saline also increased tail-flick latencies. Exposure to brief ether anesthesia or horizontal oscillation, both of which have been reported to increase ACTH secretion (a commonly used indicator of stress), did not produce analgesia as measured by the tail-flick test. The use of classical conditioning procedures to pair shock with environmental stimuli resulted in increased tail-flick latencies. The narcotic antagonist naloxone (1 mg/kg, i.p.) did not reduce the tail-flick inhibition produced by shock, rotation, hypertonic saline or classical conditioning. Chlordiazepoxide (5 mg/kg, i.p.) also failed to antagonize the increased tail-flick latencies produced by shock or conditioning. Tail-flick inhibition produced by shock or rotation was markedly reduced by complete spinal cord transection at thoracic levels. These results suggest that: (1) the selective modulation of nociceptive input at the level of the spinal cord can be mediated by a supraspinal system or systems physiologically distinct from those involved in analgesia produced by the administration of opiates; (2) non-narcotic modulation of nociceptive input occurring within the spinal cord can be learned by exposure to classical conditioning procedures; and (3) noxious stimuli are sufficient but not necessary to produce a non-narcotic analgesia; stress alone, however, is not always sufficient to produce this analgesia.     

A permissive role of corticosterone in an opioid form of stress-induced analgesia: blockade of opiate analgesia is not due to stress-induced hormone release

The 100 inescapable tail-shock paradigm produces three sequential analgesic states as the number of shocks increases: an early opioid analgesia (after 2 shocks) that is attenuated by systemic naltrexone, a middle analgesia (after 5–40 shocks) that is unaffected by systemic naltrexone, and a late opioid analgesia (after 80–100 shocks) that is attenuated by systemic naltrexone. In order to determine whether the absence of adrenal hormones would affect any of these analgesias, we tested adrenalectomized (ADX) versus sham-operated control rats 2 weeks post-surgery. Pain threshold was assessed using the tail-flick (TF) test. ADX attenuated both the early (2 shock) and late (80–100 shock) opiate analgesias and failed to reduce the naltrexone-insensitive analgesia after 5–40 shocks. We demonstrated that a loss of adrenomedullary catecholamines does not underlie the ADX-induced attenuation of opioid analgesia since sympathetic blockade using systemic chlorisondamine (6 mg/kg) failed to reduce analgesia at any point in the shock session. It was further shown that stress levels of adrenal hormones are not critical since (a) analgesia was unaffected when animals were tested 48 h after ADX, (b) 2 shocks do not produce a surge in corticosterone (CORT) over and above levels observed in animals restrained and TF tested in preparation for shock, and (c) basal CORT replacement in drinking water fully restored analgesia in ADX rats. These experiments demonstrate that basal CORT, rather than adrenomedullary substances, is critical to the expression of analgesia. The function of CORT here is not linked to a shock-induced surge of the steroid. CORT appears to play a permissive role in the expression of analgesia. Potential effects of the absence of corticosteroids on neurotransmitter biosynthesis important in analgesia production are discussed.     

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.     

Endogenous opioid immunoreactivity in rat spinal cord following traumatic injury

It has been postulated that endogenous opioids play a pathophysiological role in spinal cord injury, based on the therapeutic effects of the opiate receptor antagonist naloxone in certain experimental models. The high doses of naloxone required to exert a therapeutic action suggest that naloxone's effects may be mediated by non-mu opiate receptors, such as the kappa receptor. This notion is supported by recent pharmacological studies demonstrating that an opiate antagonist more active at kappa sites is effective and far more potent than naloxone in improving outcome after spinal cord injury. Moreover, dynorphin--postulated to be the endogenous ligand for the kappa receptor--is unique among opioids in producing hindlimb paralysis following intrathecal administration in the rat. In the present studies we have examined changes in endogenous opioid immunoreactivity following traumatic spinal cord injury in the rat. Dynorphin A was found to increase progressively with graded injury; changes were restricted to the injury segment and adjacent areas and were time dependent. Dynorphin A-(1-8) showed no marked changes. Methionine and leucine enkephalin were either unaltered or reduced at the injury site; changes were not well localized and were not clearly related to the injury variables. These findings provide further support for a potential pathophysiological role of prodynorphin-derived peptides in spinal cord injury.     

Neuroendocrine, biogenic amine and behavioral responsiveness to a repeated foot-shock-induced analgesia (FSIA) stressor in Sprague-Dawley (CD) and Fischer-344 (CDF) rats

The neurobehavioral responsiveness of two strains of rats, Fischer-344 (CDF) and Sprague-Dawley (CD), to a repeated foot-shock-induced analgesia (FSIA) stress was compared in this study. Rats were either restrained or freely moving during shock presentation (sham controls were exposed to the shock environment only). The foot-shock (15-s, 1.5-mA scrambled electric shock) was observed to induce analgesia in the CDF, but not the CD strain following acute presentation; analgesia was evaluated using time for tail-withdrawal from hot water (55 degrees C). Both strains exhibited an analgesic response when latency to tail withdrawal was evaluated just prior to daily FSIA presentations over 15 total sessions indicating that these rat strains were behaviorally conditioned to this repeated stressor. However, the levels of conditioned analgesic responses to foot-shock were: greater in the CDF and most evident when rats were restrained on the shock-grid while being administered the foot-shock. All rats were quickly sacrificed following the 15th conditioning session to determine the effects of this stressor on neurotransmitter and neuroendocrine function in both strains of rat. Experimental subjects were exposed to the shock grid but not shocked during this last session. The following was found: plasma corticosterone (CORT) and prolactin levels and adrenal CORT levels were significantly increased by repeated stress in the CDF strain; only plasma CORT levels were elevated in the CD rat; pituitary immunoreactive beta-endorphin levels were significantly higher (+46%) amongst all experimental groups in the CDF strain, but stress was not observed to alter peptide steady-state levels in either strain; dopamine (DA), 5-hydroxytryptamine and metabolites (5-hydroxyindoleacetic acid and dihydroxyphenylacetic acid) levels were generally higher in the hypothalamus and frontal cortex of the CDF rat but turnover rates (implied from metabolite/amine ratios) indicated that these systems were more sluggish in this rat strain; hypothalamic DA turnover was significantly attenuated by repeated FSIA + restraint in both strains, but the dynamics of this effect appeared to be different between rat strains; and frontal cortex 5-HT turnover was significantly elevated by repeated FSIA + restraint in only the CDF rat. This research indicates that the CDF rat is extremely sensitive to an acute FSIA stress and it is less able than the CD rat to adapt to repeated presentation of this stress.