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Biomedical subjects

L R Watkins

Publications and source records attributed to L R Watkins.

At least 127 records · Page 7Linked to original sources
PubMed1992

Spatial summation in human thermal pain perception: comparison within and between dermatomes.

Spatial summation of thermal pain has recently been reported when stimulus presentations were restricted within a single dermatome. The present study examined whether the magnitude of spatial summation of human thermal pain perception would vary when stimuli were presented within vs. between adjacent dermatomes. Noxious contact heat stimuli from 43 degrees C to 51 degrees C (5 sec duration) were applied to the forearm using areas of 0.21-2.10 cm2. Subjects rated the intensity and unpleasantness of pain using visual analog scales. For stimuli from 45 degrees C to 51 degrees C, there was a significant increase in ratings with increasing stimulus area for both intensity and unpleasantness. When two thermodes were used simultaneously in adjacent dermatomes, the ratings did not differ significantly from those for the same stimulus area in a single dermatome. We conclude that spatial summation both within and between dermatomes plays a significant role in thermal pain perception across the range from threshold to tolerance.

Adult↗
PubMed1992

A 9L gliosarcoma transplantation model for studying adoptive immunotherapy into the brains of conscious rats.

A rat model for brain tumor immunotherapy is described that closely mimics the type of treatment that could be administered to humans. It involves surgical implantation of a permanent cannula in the brain, through which tumor cells and various effector cells and/or cytokines can be injected. The advantage of this system over more conventional animal surgical procedures is that conscious animals can be treated multiple times while avoiding morbidity and mortality associated with reoperative procedures. Using this system to study adoptive immunotherapy for brain tumors, we provide evidence that the 9L gliosarcoma tumor from the Fischer rat strain can be reduced or destroyed in situ following adoptive immunotherapy with specifically activated cytotoxic T lymphocytes.

Animals↗
PubMed1991

Comparison of human pain sensation and flexion withdrawal evoked by noxious radiant heat.

The purpose of this study was to determine the reliability of flexion withdrawal magnitude as an indicator of pain sensation. In 10 healthy human volunteers, we compared the magnitude and latency of integrated biceps EMG with the subjects' rating of pain, using a visual analog scale, elicited by noxious radiant heat stimuli applied to the dorsal forearm. The magnitude and inverse latency of withdrawal, although variable, increased exponentially as a functions of stimulus temperature. The stimulus response functions for mean withdrawal magnitude and mean pain intensity were similar for lower stimulus temperatures, but at higher temperatures the withdrawal continued to increase exponentially whereas pain intensity reached a plateau. The pain intensity and withdrawal magnitude for each stimulus were poorly correlated. Under the conditions of this experiment, mean pain intensity and mean withdrawal magnitude were both well correlated with stimulus temperature, but the magnitude of withdrawal did not reliably reflect the intensity of pain sensation.

Adult↗
PubMed1990

Phenylephrine-induced antinociception: investigations of potential neural and endocrine bases.

Acute hypertensive states can produce antinociception, largely via unknown mechanisms. The aim of the present series of experiments was to examine potential hormonal and neural bases of analgesia induced by i.v. infusion of the pressor (hypertensive) agent phenylephrine. All rats were implanted with right jugular and left carotid cannulae for phenylephrine infusion and blood pressure/heart rate monitoring, respectively, and were tested approximately 24 h later in the unanesthetized state. The tail-flick test was used to measure responsivity prior to, during, and after phenylephrine infusion. Potential adrenal and pituitary contributions to phenylephrine-induced antinociception were examined, respectively, by physical disruption of adrenal blood flow and pharmacological suppression of pituitary activation. Acute block of all adrenal hormones, via closure at the time of testing of pre-implanted adrenal ligatures, did not block phenylephrine antinociception. However, pharmacological suppression of pituitary activation via pretreatment with the synthetic glucocorticoid dexamethasone abolished phenylephrine antinociception. Intriguingly, dexamethasone had no noticeable effect on urination prior to phenylephrine administration, yet only dexamethasone-treated rats exhibited copious urination during phenylephrine infusion. This suggests that the hypertensive agent phenylephrine releases vasopressin from the posterior pituitary terminals of the paraventricular hypothalamus (PVH) in a dexamethasone-suppressible manner, possibly via the known baroreceptor-nucleus tractus solitarius (NTS)-PVH link. Since (1) bilateral lesions of the spinal cord dorsolateral funiculus (DLF) were shown in the current study to abolish phenylephrine antinociception, (2) PVH is known to send vasopressinergic projections to the spinal cord via the DLF, and (3) intrathecal vasopressin produces antinociception via V1-like vasopressin receptors, the effect of an intrathecal V1 vasopressin antagonist was tested on phenylephrine-induced antinociception. The V1 vasopressin antagonist blocked phenylephrine antinociception, suggesting that phenylephrine antinociception may be mediated by a baroreceptor-NTS-PVH-DLF circuit leading to vasopressin release at spinal levels.

Adrenal Glands↗
PubMed1989

Electrical stimulation of the rat ventral midbrain elicits antinociception via the dorsolateral funiculus.

The pain-suppressive effects of focal electrical stimulation of sites throughout the ventral midbrain were examined in awake rats. Chronic bipolar electrodes were implanted in medial and lateral regions of the midbrain. Current thresholds for suppression of the tail-flick reflex in response to noxious heat were determined for both a biphasic and a monophasic stimulation parameter at each site. Stimulation of areas throughout the ventral midbrain produced tail-flick suppression (TFS), but no one area was consistently effective in all animals. Monophasic and biphasic stimulation were qualitatively equal in the duration of TFS and the distribution of effective sites. The production of TFS was not correlated with other behavioral reactions to brain stimulation. TFS appeared to be mediated by non-opiate pathways since naloxone administration (10 mg/kg) had no discernible effect on the production of TFS. The current threshold for producing TFS was extremely variable over both short (one half hour) and long (one week) intervals. The incidence of TFS from previously effective sites was significantly less following bilateral dorsolateral funiculus (DLF) lesions, indicating that the antinociceptive effects of ventral midbrain stimulation are mediated by this spinal pathway.

Analgesia↗
PubMed1988

Antinociception vs motor effects of intrathecal vasopressin as measured by four pain tests.

The effects of intrathecal (i.t.) vasopressin (VP) on nociception were quantitatively tested in rats using 4 pain tests: tail flick, tail shock vocalization, hot plate, and formalin. In addition, motor effects of VP were examined qualitatively. I.t. VP produced a prolonged antinociception lasting at least 40 min on the tail flick (2.5 and 25 ng) and formalin (25 ng) tests, and a brief antinociception lasting less than 20 min on the tail shock (25 ng) and hot plate (25 ng) tests. Those rats not responding to the pain tests showed no signs of perceiving the pain stimulus, such as orientation to the stimulus or vocalization. In addition, i.t. VP produced scratching bouts (2.5 and 25 ng) and suppressed hindbody motor function (25 ng). The motor inhibitory effects of VP, although severe in some rats, were brief, lasting less than 15 min. In conclusion, i.t. VP produces antinociception in addition to its motor effects, and these properties appear to be due to separate mechanisms.

Animals↗
PubMed1988

The dorsal raphe nucleus: a re-evaluation of its proposed role in opiate analgesia systems.

Previous studies have concluded that (a) electrical stimulation in the periaqueductal gray/dorsal raphe nucleus (PAG/DRN) region specifically produces either non-opiate or opiate forms of antinociception dependent upon the dorsoventral level of stimulation and (b) the 'opiate' form of stimulation-produced analgesia (SPA) arising from the ventral PAG/DRN region shows cross-tolerance with opiate forms of footshock analgesia, implying common neural substrates. This latter conclusion in turn implies that SPA elicited from the ventral PAG/DRN region would be expected to be antagonized by scopolamine, since this muscarinic cholinergic antagonist blocks opiate footshock analgesia. The present study demonstrates instead that neither 10 mg/kg naloxone nor 10 mg/kg scopolamine had any effect on SPA elicited from sites histologically verified to lie within the presumptive 'opiate' ventral PAG/DRN region. These data bring into question both the site specificity of opiate SPA and the common mediation of ventral PAG/DRN SPA and opiate forms of footshock analgesia.

Analgesia↗
PubMed1986

Inhibition of the responses of neurons in the rat spinal cord to noxious skin heating by stimulation in midbrain periaqueductal gray or lateral reticular formation.

Single units responsive to noxious heating of glabrous hindfoot skin were recorded in the lumbar spinal cord of rats anesthetized with sodium pentobarbital. Unit responses to heat stimuli (e.g. 50 degrees C, 10 s) delivered at 2-min intervals were stable and were markedly suppressed during stimulation (100-ms pulse trains at 100 Hz, 3/s, 25-400 microA) in the midbrain periaqueductal gray (PAG) or lateral reticular formation (LRF). Inhibition did not appear to outlast the midbrain stimulation period. By systematically varying the position of an array of 3 or 5 stimulating electrodes, we observed that stimulation in PAG and subjacent tegmental areas, as well as in widespread regions of the LRF bilaterally, suppressed unit responses to noxious skin heating. The degree of suppression of unit responses increased with graded increases in PAG or LRF stimulation intensity. LRF appeared to be more efficacious than PAG stimulation, based on lower currents at threshold, as well as on significantly greater slopes in current-inhibition plots for LRF compared to PAG stimulation. Unit responses increased linearly with graded increases in stimulus temperature from 42 to 54 degrees C. Slopes of temperature-response lines were reduced during PAG stimulation with no change in response threshold, while temperature-response lines were shifted in a parallel manner toward higher temperatures during LRF stimulation with an increase in response threshold. The results suggest that differential inhibitory systems are activated by PAG or LRF stimulation and are discussed in relation to previous findings in the cat and as a possible mechanism of stimulation-produced analgesia.

Animals↗
PubMed1986

Role of spinal cord neuropeptides in pain sensitivity and analgesia: thyrotropin releasing hormone and vasopressin.

The existence of a wide variety of neuropeptides within the spinal cord dorsal horn raises the question of their possible roles in sensory processing. The present series of behavioral experiments examined the effects of intrathecal (IT) administration of two such neuropeptides, thyrotropin-releasing hormone (TRH) and vasopressin (VAS), on pain sensitivity and antinociception. TRH exerted no marked effect on basal pain sensitivity over the dose range examined (0.25 ng-2.5 micrograms). However, a U-shaped dose-response effect on morphine antinociception (3 micrograms, IT) was observed, wherein potent attenuation, moderate attenuation, or enhancement of morphine-induced antinociception was observed following the various doses tested. In contrast, VAS produced non-opiate antinociception at the highest doses tested (25 ng and 250 ng) and none of the VAS doses (0.25 ng-250 ng) appeared to interact with IT morphine (3 micrograms) antinociception. Lastly, IT TRH was not observed to interact with IT VAS antinociception. These data provide evidence that these neuropeptides exert strikingly different effects on pain sensitivity and opiate antinociception, and provide initial evidence that TRH may be included in the growing list of neuropeptides that can act like endogenous opiate antagonists within the central nervous system.

Analgesia↗
PubMed1985

Sexual responsiveness and its relationship to vaginal stimulation-produced analgesia in the rat.

Increasing amounts of pressure applied to the cervix produce a dose-response-like elevation of pain threshold in rats. This vaginal stimulation-produced analgesia (VSPA) is facilitated in animals given estrogen (E) doses sufficient to induce high levels of sexual receptivity. It has been proposed that enhancement of VSPA may serve to decrease any noxious input associated with multiple intromissions by the male. In this study, the anti-nociceptive effect of VSPA was compared in animals given E doses insufficient to increase receptivity with animals made receptive using subthreshold E levels + progesterone (P) in an attempt to determine if enhancement of VSPA is associated with the receptive state of the animal or the dose of E used. Tail flick latencies and tail shock vocalization thresholds were measured in groups of E, E + P and oil-treated rats during application of 0, 100 and 200 g of force on the cervix. Within oil, E and E + P-treated animals, significant increases in tail flick latencies were observed at 100 and 200 g with respect to baseline (0 g). Moreover, at 100 g of force E treated animals displayed a significant increase in tail flick latency over oil and E + P treated rats. In contrast, tail shock vocalization was increased at 100 and 200 g levels of probing in oil and E + P groups but was not facilitated by E. In the present study, as in previous work, VSPA was potentiated by E; however, this potentiation was not correlated with steroid-induced receptivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1985

Spinal pain suppression mechanisms may differ for phasic and tonic pain.

The dorsolateral funiculus (DLF) spinal pathway has previously been identified as a major pathway involved in descending modulation of pain. While bilateral lesions of the DLF attenuated systemic morphine analgesia as measured by the tail-flick test, they failed to attenuate analgesia as measured by the formalin test. These results suggest that phasic and tonic pain, modeled by the tail-flick and formalin tests, respectively, may utilize different pain suppression mechanisms.

Animals↗
PubMed1985

Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide.

Recent evidence has suggested that cholecystokinin (CCK) may act as a physiological opiate antagonist. Both the overlap of CCK and opiate systems within the central nervous system and the fact that exogenous CCK can antagonize opiate analgesia suggest that endogenous CCK systems interact with opiate-mediated pain inhibitory systems. In the present series of experiments, we examined the effect of the CCK receptor antagonist proglumide on various forms of morphine analgesia. We have observed that proglumide can potentiate morphine analgesia following systemic, intrathecal or intracerebral administration of these drugs. Endogenous CCK systems do not appear to be tonically active since neither systemic, intrathecal nor intracerebral proglumide typically produced measurable analgesia in the absence of morphine. These data suggest that CCK may be released in response to opiate administration and acts to return the organism toward its basal level of pain sensitivity. If such a hypothesis is in fact true, then CCK blockade may be of clinical value in the treatment of pain.

Analgesia↗
PubMed1985

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.

Analgesia↗
PubMed1984

Bilateral lesions of the dorsolateral funiculus of the cat spinal cord: effects on basal nociceptive reflexes and nociceptive suppression produced by cholinergic activation of the pontine parabrachial region.

In cats, bilateral microinjections of the cholinergic agonist, carbachol (0.6 micrograms in 0.2 microliter), into an area surrounding the lateral half of the brachium conjunctivum (BC) produces a non-narcotic suppression of nociceptive responses, as assessed by flexion reflexes (tail-flick and calibrated pinch tests). Bilateral lesions of the dorsolateral funiculi (DLF) of the thoracic spina cord (T2) significantly reduced the magnitude of this nociceptive suppression. Nociceptive suppression following carbachol microinjections into sites along the dorsal aspect of BC was reduced by DLF lesions to a greater degree than nociceptive suppression following injections into sites within or ventral to BC. Relatively superficial DLF lesions produced reductions in nociceptive suppression which were equivalent to reductions induced by deeper lesions. DLF lesions, either superficial or deep, produced equivalent, reliable decreases in tail-flick test assessments of baseline nociceptive thresholds. The magnitude of decreases in baseline nociceptive thresholds produced by DLF lesions was not correlated with the magnitude of reduction of carbachol-induced suppression of nociceptive responses, indicating that DLF lesions suppress anti-nociception independent of baseline alterations. These data suggest that non-narcotic analgesia produced by cholinergic activation of cells along the dorsal aspect of BC may be predominantly mediated by fibers descending within the DLF. However, results of the retrograde horseradish peroxidase (HRP) tracing studies reported in the present investigation indicate that this pain suppression is probably mediated by polysynaptic pathways since this region dorsal to BC projects neither through DLF nor extra-DLF pathways. Retrograde HRP data show that areas ventral to and including BC projects to the cord via both DLF and extra-DLF pathways. Since DLF lesions were less effective in reducing analgesia attained from ventral compared to dorsal sites, spinal pathways other than DLF may mediate reflex suppression following carbachol microinjection into these more ventral sites. Possible cholinergic contributions to endogenous, non-opiate forms of analgesia are discussed.

Acetylcholine↗
PubMed1984

Effect of spinal cord lesions on convulsive activity induced by intrathecal morphine.

Non-specific convulsive behavior induced by intrathecal (IT) morphine microinjection appears to be tonically modulated by centrifugal pathways originating within the brain since the frequency of IT morphine-induced hindlimb seizures and myoclonic twitches are both increased following spinal transection. These effects on convulsant activity are dissociable by selective neural lesions. Bilateral dorsolateral funiculus lesions potentiate seizure activity whereas ventral funiculus lesions and, to a lesser extent, interruption of cerebral cortical influences enhance myoclonic twitch activity. These initial studies indicate that distinct supraspinal centers differentially modulate myoclonic and seizure activity and suggest that an understanding of these systems may have clinical implications for the control of convulsant activity.

Animals↗
PubMed1984

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 muscarinic 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.

Analgesia↗