Reversal of morphine and stimulus-produced analgesia by subtotal spinal cord lesions

Basbaum, Allan I.; Marley, N. J. E.; O’Keefe, John; Clanton, Charles H.

doi:10.1016/0304-3959(77)90034-3

Cited by 298 publications

(69 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is of interest that the earliest studies of stimulation-produced analgesia pointed to the midline dorsal raphe, rather than the PAG as the critical target for generating analgesia (Mayer et al, 1971;Akil and Mayer, 1972;Guilbaud et al, 1973;Liebeskind et al, 1973;Basbaum et al, 1977). In fact, because putative serotonin antagonists blocked the analgesia and inhibition of the firing of spinal cord "pain" responsive neurons, the Besson group concluded that the 5HT neurons of the DR were key to initiating the descending controls (Guilbaud et al, 1973;Liebeskind et al, 1973).…”

Section: Output Of the Midbrain Serotonergic Neuronsmentioning

confidence: 99%

Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits

Bráz

Basbaum

2008

J of Comparative Neurology

Self Cite

View full text Add to dashboard Cite

Despite the evidence for a significant contribution of brainstem serotonergic (5HT) systems to the control of spinal cord "pain" transmission neurons, attention has turned recently to the influence of nonserotonergic neurons, including the facilitatory and inhibitory controls that originate from socalled "on" and "off" cells of the rostroventral medulla (RVM). Unclear, however, is the extent to which these latter circuits interact with or are influenced by the serotonergic cell groups. To address this question we selectively targeted expression of a transneuronal tracer, wheat germ agglutinin (WGA), in the 5HT neurons so as to study the interplay between the 5HT and non-5HT systems. In addition to confirming the direct medullary 5HT projection to the spinal cord we also observed large numbers of non-5HT neurons, in the medullary nucleus reticularis gigantocellularis and magnocellularis, that were WGA-immunoreactive, i.e., were transneuronally labeled from 5HT neurons. Fluoro-Gold injections into the spinal cord established that these reticular neurons are not only postsynaptic to the 5HT neurons of the medulla, but that most are also at the origin of descending, bulbospinal pathways. By contrast, we found no evidence that neurons of the midbrain periaqueductal gray that project to the RVM are postsynaptic to midbrain or medullary 5HT neurons. Finally, we found very few examples of WGA-immunoreactive noradrenergic neurons, which suggests that there is considerable independence of the monoaminergic bulbospinal pathways. Our results indicate that 5HT neurons influence "pain" processing at the spinal cord level both directly and indirectly via feedforward connections with multiple non-5HT descending control pathways. Indexing termsWGA; pain; serotonin; brainstem; analgesia; RVM Until recently, studies of the bulbospinal systems that originate from the rostral ventral medulla (RVM) emphasized their contribution to inhibitory control of "pain" transmission. HHS Public AccessAuthor manuscript J Comp Neurol. Author manuscript; available in PMC 2016 July 16. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptMost important, opioid injection into or electrical stimulation of the midbrain periaqueductal gray (PAG) activates these descending pathways and concurrently produces a profound antinociceptive action, including inhibition of the firing of dorsal horn nociresponsive neurons and behavioral analgesia (Basbaum and Fields, 1984). Although neurochemically distinct pathways arise from the RVM, considerable evidence pointed to the contribution of medullary serotonergic neurons. For example, morphine evokes the release of serotonin at the level of the spinal cord and RVM (Matos et al., 1992;Taylor and Basbaum, 2003) and serotonin depletion using pharmacological or ablative procedures blocks the analgesia induced by systemic administration of morphine (Vogt, 1974;Proudfit and Anderson, 1975;Yaksh et al., 1977).In agreement with these findings, Zhao et al. (2007a,b) reported that inflammatory pai...

show abstract

Section: Output Of the Midbrain Serotonergic Neuronsmentioning

confidence: 99%

Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits

Bráz

Basbaum

2008

J of Comparative Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is well established that electrical stimulation of portions of the medial brainstem can inhibit both vocalization to nociceptive stimuli and spinally mediated nociceptive reflexes (Reynolds 1969;Mayer et al 1971;Oliveras et al 1974;Akil and Liebeskind 1975;Basbaum et al 1977;Basbaum and Fields 1979). The inhibitory signal, is believed to originate in the periaqueductal gray, travel to the rostroventral medulla, including the nucleus raphe magnus (NRM), and then to the spinal cord through serotonergic fibers that descend through the DLF to suppress firing of neurons within the dorsal horns (Mayer et al 1971;Oliveras et al 1974;Fields 1979, 1984).…”

Section: Introductionmentioning

confidence: 99%

Exposure to intermittent nociceptive stimulation under pentobarbital anesthesia disrupts spinal cord function in rats

et al. 2007

View full text Add to dashboard Cite

Rationale-Spinal cord plasticity can be assessed in spinal rats using an instrumental learning paradigm in which subjects learn an instrumental response, hindlimb flexion, to minimize shock exposure. Prior exposure to uncontrollable intermittent stimulation blocks learning in spinal rats but has no effect if given before spinal transection, suggesting that supraspinal systems modulate nociceptive input to the spinal cord, rendering it less susceptible to the detrimental consequences of uncontrollable stimulation.Objective-The present study examines whether disrupting brain function with pentobarbital blocks descending inhibitory systems that normally modulate nociceptive input, making the spinal cord more sensitive to the adverse effect of uncontrollable intermittent stimulation. Materials and methods-MaleSprague-Dawley rats received uncontrollable intermittent stimulation during pentobarbital anesthesia after (experiment 1) or before (experiment 2) spinal cord transection. They were then tested for instrumental learning at a later time point. Experiment 3 examined whether these manipulations affected nociceptive (thermal) thresholds.Results-Experiment 1 showed that pentobarbital had no effect on the induction of the learning deficit after spinal cord transection. Experiment 2 showed that intact rats anesthetized during uncontrollable intermittent stimulation failed to learn when later transected and tested for instrumental learning. Experiment 3 found that uncontrollable intermittent stimulation induced an antinociception in intact subjects that was blocked by pentobarbital. Conclusions-The results suggest a surgical dose of pentobarbital (50 mg/kg) suppresses supraspinal (experiment 2) but not spinal (experiment 1) systems that modulate nociceptive input to the spinal cord by blocking the antinociception that is induced by this input (experiment 3).

show abstract

“…For example, systemic morphine was less effective in increasing the threshold in the tail flick test (which is generally accepted as a spinal reflex) in spinally transected as compared with intact rats (Advokat & Burton, 1987;Sinclair et al, 1988). Lesions of the dorsolateral funiculus or of brainstem nuclei reduced the effectiveness of systemic morphine in this test (Murfin et al, 1976;Basbaum et al, 1977;Yaksh & Rudy, 1977;Hayes et al, 1978;Barton et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

The effects of sham and full spinalization on the systemic potency of μ‐ and κ‐opioids on spinal nociceptive reflexes in rats

Herrero

Headley

1991

British J Pharmacology

View full text Add to dashboard Cite

1 Flexor withdrawal reflexes to noxious mechanical pinch stimuli were recorded as single motor unit activity in a-chloralose anaesthetized rats, by means of tungsten bipolar electrodes inserted percutaneously into hindlimb flexor muscles. The relative spinal and supraspinal contributions to y-and K-opioid agonists in inhibiting these spinal reflexes, together with possible potency changes elicited by surgical trauma, were examined by comparing their relative potencies in spinally unoperated, sham spinalized and spinalized rats. 2 The noxious stimuli, which were of comparable intensity in the three groups, elicited similar mean firing rates of the motor units in all groups. This indicates that the excitability levels in the reflex pathway were not greatly affected by either sham or actual spinalization. 3 The ,-agonists morphine and fentanyl, and the K-agonist U-50,488H, inhibited the reflexes in a dosedependent manner, when administered intravenously in a log2 cumulative dose regime. 4 The surgery of sham spinalization had little effect on the potency of morphine and fentanyl, whereas it doubled the potency of U-50,488. 5 Spinalization did not affect the potency of morphine. In contrast it decreased the potency of fentanyl 2-4 fold and that of U-50,488 approximately 6 fold. 6 The effects of all agonists were antagonized by naloxone. Dose-dependence studies indicating that antagonism of U-50,488H required about 5 times the dose of naloxone that antagonized morphine. 7 The data suggest that surgical trauma to the spinal column and/or dura mater triggers supraspinal mechanisms that significantly enhance the potency of K-but not P-agonists.8 It is concluded that most of the effects of systemic morphine on spinal reflexes are mediated, under all three conditions tested, by direct effects in the spinal cord. In contrast, the inhibition of reflexes by U-50,488H is mediated at both spinal and supraspinal levels, the latter being enhanced in the presence of surgical trauma. The differences between morphine and fentanyl remain unexplained.

show abstract

Reversal of morphine and stimulus-produced analgesia by subtotal spinal cord lesions

Cited by 298 publications

References 27 publications

Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits

Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits

Exposure to intermittent nociceptive stimulation under pentobarbital anesthesia disrupts spinal cord function in rats

The effects of sham and full spinalization on the systemic potency of μ‐ and κ‐opioids on spinal nociceptive reflexes in rats

Contact Info

Product

Resources

About