Front Paw Shock Research Articles

Activation of anti- and pro-nociceptive mechanisms by front paw shock in spinal mice: Involvement of humoral factors

The effect of prolonged, intermittent front paw shock on nociception was studied in two groups of differently spinalized mice. The animals, spinalized so that the dura was left intact to allow free cerebrospinal fluid (CSF) passage, exhibited post-foot shock increase in latencies of spinally-mediated nociceptive reflexes. This anti-nociception was completely blocked by naloxone. A facilitation of nociceptive reflexes was observed in animals in which the spinal cord was ligated together with the dura. The results indicate that: (1) front paw in mice leads to activation of supraspinal sites which mediate anti-nociception by releasing substance(s) reaching the spinal cord via the CSF route; (2) single stressors may simultaneously activate both anti- and pro-nociceptive mechanisms.

Environmentally induced analgesia: an age-related decline in an endogenous opioid system.

The purpose of the present study was to examine in rats the relationship between the age-related decline in an opioid receptor system and the function of the endogenous opioid pain-inhibitory system activated by front-paw shock. Results revealed that the analgesia displayed following front-paw shock declined between 5- to 7-month-old, 15- to 17-month-old, and 22- to 24-month-old age groups. The administration of naloxone significantly attenuated the shock-induced analgesia. Thus, the endogenous opioid pain modulatory system activated by front-paw shock (the nucleus raphe alatus and a descending pathway lying within the dorsolateral funiculus of the spinal cord) declines in function with increasing age. This research also confirms that there is a parallel between the age-related decline in the neurochemical indexes of the opioid receptor system and the function of these receptors in producing analgesia in response to aversive stimulation.

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.

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.

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.

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 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.

Opiate vs non-opiate eootshock induced analgesia (FSIA): Descending and intraspinal components

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.

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.

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) has recently been observed to be differentially elicited dependent upon the body region shocked; front paw and hind paw shock produce opiate and non-opiate analgesia, respectively. Previous studies have shown that footshock can also produce classically conditioned analgesia; that is, when shock is delivered to an animal, environmental cues become associated with the noxious stimulus such that these cues become capable, in and of themselves, of producing potent analgesia. The present series of experiments examined analgesia classically conditioned to either front paw or hind paw shock. The non-electrified shock grid served as the conditioned stimulus (CS), 90-s footshock as the unconditioned stimulus (UCS) and tail-flick inhibition as the unconditioned response (UCR). Following CS-UCS pairings, exposure to the non-electrified grid reliably produced prolonged analgesia. This classically conditioned analgesia appears to involve endogenous opioids, regardless of the body region shocked during conditioning trials, since the analgesia is attenuated by systemic naloxone and shows cross-tolerance to morphine. A spinal opioid site is involved since 1 μg of naloxone delivered directly to the lumbosacral cord antagonizes the analgesia. Like front paw (opiate) FSIA, CCA can be prevented but cannot be reversed by naloxone; naloxone can antagonize classically conditioned analgesia only if it is delivered prior to exposure to the conditioned stimulus. Lastly, a similarity was recognized between classically conditioned analgesia and the analgesias induced by morphine, brain stimulation, front paw shock and hind paw shock in that all are mediated via descending pathways within the dorsolateral funiculus of the spinal cord.

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.

Involvement of spinal opioid systems in footshock-induced analgesia: Antagonism by naloxone is possible only before induction of analgesia

Footshock reliably produces analgesia in rats which is mediated either by opiate or non-opiate systems. It has recently been demonstrated that a critical factor determining the involvement of endogenous opioids is the body region shocked; front paw shock produces a naloxone-reversible analgesia and hind paw shock produces an analgesia which fails to be attenuated by this opiate antagonist. The present study demonstrated that a crucial opiate site for the production of front paw footshock-induced analgesia (FSIA) exists within the spinal cord. One μg of naloxone delivered directly to the lumbosacral cord immediately prior to shock significantly attenuated this analgesia. However, the efficacy of naloxone antagonism was order-dependent in that naloxone failed to antagonize front paw FSIA if delivered immediately after shock; naloxone could prevent but could not reverse the analgesic state. The body region shocked was again observed to be a critical factor determining the involvement of endogenous opioids since 1 μg of spinal naloxone failed to antagonize hind paw FSIA. These results were discussed in light of recent evidence proposing a neuromodulatory role of opioids within the spinal cord.