Biomedical subjects

L R Watkins

Publications and source records attributed to L R Watkins.

At least 145 records · Page 8Linked to original sources

PubMed1984

Evidence for involvement of cholinoceptive cells of the parabrachial region in environmentally induced nociceptive suppression in the cat.

We have previously observed that activation of muscarinic receptors within the pontine parabrachial region (PBR) of cats produces potent analgesia. This study demonstrated that bilateral microinjections of the muscarinic antagonist atropine (each 4.0 micrograms in 1.0 microliter) into PBR attenuated nociceptive suppression elicited by exposure of cats to novel environmental changes without affecting general responsiveness to environmental stimulation. This observation suggests that muscarinic cholinoceptive cells in PBR function physiologically to modulate nociceptive responsiveness in response to certain environmental stimuli.

Animals↗

PubMed1984

Differential behavioral effects induced by intrathecal microinjection of opiates: comparison of convulsive and cataleptic effects produced by morphine, methadone, and D-Ala2-methionine-enkephalinamide.

Intrathecal (i.t.) microinjection of 400 micrograms of morphine in rats induces convulsive activity restricted to the hindlimbs. This activity is potentiated rather than antagonized by naltrexone, is potentiated in animals pretreated over 6 days with increasingly higher systemic doses of morphine, and is potentiated and prolonged by high thoracic spinalization . Similar to morphine, convulsive spinal activity could also be elicited with i.t. injection of the non-opiate convulsant penthylenetetrazol (PTZ). However, methadone, D-ala2-methionine-enkephalinamide (DALA), or naltrexone, injected i.t. at equimolar doses with morphine did not produce similar convulsive behavior. DALA and methadone rather produced pronounced spinal catalepsy. It was concluded: that the spinal convulsive action of morphine is not mediated by specific opiate receptors; and that the spinal cord may be one of the sites where high doses of systemically administered morphine may produce convulsions.

Animals↗

PubMed1984

Cataleptic effects of opiates following intrathecal administration.

Intrathecal (i.t.) administration of D-ala2-methionine-enkephalinamide (DALA) and methadone induces pronounced hindlimb catalepsy in rats. DALA is more potent than methadone in inducing this behavior and catalepsy induced by both compounds is partially blocked by prior treatment with naltrexone. Intrathecal morphine induces convulsive hindlimb activity at doses of 25, 100 and 400 micrograms. However, only the highest dose produces indications of cataleptic behavior. It is suggested that whereas the convulsive behavior induced by i.t. morphine is not mediated by specific opiate receptors, catalepsy induced by all 3 compounds is.

Animals↗

PubMed1984

Nonspecific convulsions are induced by morphine but not D-Ala2-methionine-enkephalinamide at cortical sites.

Cortical application of morphine (25, 100 and 400 micrograms) induced cortical spikes in a dose-related fashion and, at 400 micrograms, behavioral and electrographic seizures. These electrographic seizures were not opiate specific since this activity occurred undiminished in naltrexone-pretreated animals and was even potentiated in animals pretreated for 6 days with increasingly higher doses of systemic morphine. In contrast to the effects induced by morphine, the most consistent electrographic effect of cortically applied D-Ala2-methionine-enkephalin (DALA) and methadone was a depression of cortical EEG. These results support the hypothesis that the cortex and spinal cord together form the anatomical substrate of the documented nonspecific convulsive action of high systemically administered doses of morphine.

Animals↗

PubMed1984

Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide.

Exogenous cholecystokinin selectively antagonizes opiate analgesia, which suggests that endogenous cholecystokinin may act physiologically as an opiate antagonist and may play a role in opiate tolerance. The use of the selective cholecystokinin antagonist proglumide provided a test of these hypotheses in rats that were either inexperienced with or tolerant to opiates. Proglumide potentiated analgesia produced by morphine and endogenous opiates and seemed to reverse tolerance. These results suggest that endogenous cholecystokinin systems oppose the action of opiates.

Analgesia↗

PubMed1984

Fear is not critical to classically conditioned analgesia: the effects of periaqueductal gray lesions and administration of chlordiazepoxide.

A high correlation between fear and analgesia classically conditioned to footshock in rats has been reported in the literature. However, it has never been directly tested whether or not fear is in fact causal to the production of conditioned analgesia. We therefore tested whether conditioned analgesia could be elicited in the absence of fear by employing two independent methods of fear suppression. First, areas of the periaqueductal gray (PAG) previously implicated in fear were selectively lesioned. Lesions of the dorsolateral PAG significantly attenuated conditioned analgesia and markedly decreased fear responses. Second, fear was attenuated via administration of chlordiazepoxide (CDP). Rats which had been conditioned while in the presence of CDP showed no reduction in conditioned pain inhibition. These results demonstrate that: (1) fear is not causal to classically conditioned analgesia and (2) the anatomical substrates for fear and conditioned analgesia are distinct but partially overlapping. The fact that fear is not a critical antecedent for classically conditioned analgesia suggests that classical conditioning techniques may be applied clinically to increase the effectiveness of some analgesic manipulations.

Animals↗

PubMed1984

Non-opiate analgesia induced by carbachol microinjection into the pontine parabrachial region of the cat.

These studies investigated the effect of microinjection of the cholinergic agonist carbamylcholine (carbachol) into various sites of the dorsolateral pontine tegmentum of the cat. Carbachol microinjection into an area surrounding the lateral half of the brachium conjunctivum (parabrachial region, PBR) produced profound suppression of nociceptive responses. In the dorsal part of PBR, carbachol microinjection produced no generalized sensory, emotional or motor deficits, indicating that nociceptive transmission was primarily affected. Carbachol microinjection into the ventral part of PBR resulted in slight suppression of motor responses in addition to profound nociceptive suppression. Carbachol-produced analgesia (CPA) observed within PBR blocked supraspinally as well as spinally integrated responses normally elicited by either phasic or tonic noxious stimuli. Atropine sulfate, but not mecamylamine hydrochloride, significantly antagonized CPA, indicating that muscarinic receptors mediate this phenomenon. The opiate antagonist naloxone, systemically administered either prior to or after carbachol microinjection, did not reliably attenuate CPA. Microinjection of morphine into the sites from which CPA had previously been obtained did not produce significant effects on nociceptive responses. Thus, opiate mechanisms appear not to be necessary either for the activation of this system or for the production of the resultant analgesia. These findings indicate that the neural population examined in the present study is anatomically and pharmacologically distinct from previously identified opiate-mediated pain inhibitory systems. Results are discussed in light of other recent evidence indicating the existence of endogenous non-opiate pain inhibitory systems.

Animals↗

PubMed1984

Dorsolateral funiculus and intraspinal pathways mediate vaginal stimulation-induced suppression of nociceptive responding in rats.

In rats, stimulation of the vaginal cervix with a glass rod reliably produces analgesia, as measured by the tail-flick test. The present studies sought to identify the neural substrates underlying this potent pain inhibition by examining the effects of decerebration, spinalization and bilateral dorsolateral funiculus (DLF) lesions on vaginal stimulation-produced analgesia (VSPA). These studies indicate that the neural circuitry mediating VSPA is contained within the caudal brainstem and spinal cord, since decerebration did not reduce VSPA when compared with sham-operated controls. A significant though markedly reduced level of analgesia was induced in spinalized rats, indicating that VSPA involves both intraspinal and descending pathways. This descending pathway, originating within supraspinal nuclei of the caudal brainstem, projects to the spinal cord via the DLF, since DLF lesions and spinalization produced equivalent reductions in VSPA compared to sham-operated controls. These results, considered in the light of previous electrophysiological and anatomical findings, indicate that the ventral medullary region may be the source of the descending DLF projection mediating VSPA.

Animals↗

PubMed1984

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.

Animals↗

PubMed1984

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.

Afferent Pathways↗

PubMed1984

Comparison of the effects of ventral medullary lesions on systemic and microinjection morphine analgesia.

The effects of electrolytic lesions of the nucleus raphe magnus (NRM), nucleus reticularis paragigantocellularis (PGC) and nucleus raphe alatus (NRA) on analgesia elicited in the rat from systemic morphine and morphine microinjection into the periaqueductal gray (PAG) were evaluated using the tail flick test. No consistent change in baseline pain sensitivity was observed following lesions of the NRM, PGC or NRA. To determine the effect of ventral medullary lesions on systemic morphine analgesia, pain sensitivity was assessed prior to and 40 min after 6 mg/kg morphine administration (i.p.) at 2 days preceding lesioning and 5, 12 and 19 days post-lesion. NRM and PGC lesions produced only slight reductions in analgesia at 5 days after surgery. It was observed that large NRM, large PGC, and NRA lesions significantly attenuated analgesia evaluated at 12 days post-lesion. Smaller lesions confined within the NRM or PGC were reliably less effective than the larger lesions in reducing analgesia. In a subsequent study, 5 micrograms morphine in 0.5 microliter saline was microinjected into the ventral PAG at the level of the dorsal raphe. Identical testing procedures were used and the analgesia was assessed at 2 days before lesioning and 5 and 12 days post-lesion. In contrast to the previous study, large NRM lesions abolished analgesia as early as 5 days following lesioning. Small NRM lesions were less effective and PGC lesions were generally ineffective in attenuating analgesia induced by morphine microinjection. We conclude that the NRA may act as a functional unit in the mediation of systemic morphine analgesia. In contrast, analgesia elicited from intracerebral (PAG) morphine microinjection is mediated via the NRM.

Analgesia↗

PubMed1984

A psychophysical analysis of acupuncture analgesia.

A psychophysical analysis of acupuncture analgesia was carried out in which low back pain patients made visual analogue scale (VAS) responses both to their chronic pain and to different levels of experimental heat pain (5 sec exposures to 43-51 degrees C) before and after electroacupuncture. VAS (sensory) responses to chronic pain, direct temperature matches to chronic pain, and VAS (sensory) responses to experimental pain were reduced in an internally consistent manner 1-2 h after treatment. The magnitude of this analgesic response was similar for dermatomes within the region of chronic pain and acupuncture needle placement (lower back) as well as for dermatomes remote from needle placement and chronic pain (forearm). Individual patients manifested either (1) a central-inhibitory pattern of analgesia wherein experimental and chronic pain in back regions and experimental pain in forearm regions were reduced, or (2) an origin-specific pattern wherein only the chronic low back pain was reduced. Patients tested several days after treatment all manifested the latter pattern of analgesia. VAS sensory and VAS affective analgesic responses to electroacupuncture treatment showed a delayed onset (1-24 h) to maximum effect and a duration of 10-14 days. Cumulative sensory and affective analgesic effects were observed at the end of 4 months of biweekly acupuncture treatments. The results of this analysis reveal the unique spatial and temporal properties of electroacupuncture analgesia and the extent to which it is mediated by at least two different mechanisms.

Acupuncture Therapy↗

PubMed1984

Non-serotonergic origins of the dorsolateral funiculus in the rat ventral medulla.

Cells within the ventral medulla whose axons descend to the spinal dorsal horn via the dorsolateral funiculus (DLF) play an important role in pain modulation. Previous evidence suggests that this pathway is primarily serotonergic. We have examined this hypothesis directly using combined retrograde horseradish peroxidase/serotonin immunohistochemical staining. Cells of the ventral medulla contributing to the DLF were found to be largely non-serotonergic. This result was confirmed by two approaches: by the absence of a significant number of double-labeled cells following discrete horseradish peroxidase labeling of the DLF and by the persistence of double-labeled cells in animals with DLF lesions made rostral to intraspinal injections of horseradish peroxidase solutions. The conclusion is made that the previously described nucleus raphe magnus-DLF-dorsal horn pathway is predominantly non-serotonergic.

3,3'-Diaminobenzidine↗

PubMed1983

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 raphe 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.

Analgesia↗

PubMed1983

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 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.

Analgesia↗

PubMed1983

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.

Analgesia↗

PubMed1983

Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia.

The endogenous neuropeptide cholecystokinin, when administered systemically or perispinally, potently antagonizes opiate analgesia produced by foot shock and morphine. Nonopiate foot-shock analgesia is not reduced by this neuropeptide. The spinal cord appears to be a critical site of cholecystokinin action. These experiments suggest a physiological role for cholecystokinin as a specific opiate antagonist in analgesia-mediating systems. A similar mode of action may explain other behavioral effects of cholecystokinin, such as suppression of food intake.

Animals↗

PubMed1982

Footshock induced analgesia is dependent neither on pituitary nor sympathetic activation.

A variety of environmental stimuli have been demonstrated to produce 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 plain 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 beta-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.

Adrenalectomy↗