Naloxone reversal of analgesia produced by brain stimulation in the human

Adams, John E.

doi:10.1016/0304-3959(76)90111-1

Cited by 251 publications

(58 citation statements)

References 7 publications

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“…The naloxone doses (2 and 10 mg) given here by the intravenous route were certainly more than sufficient. For comparison, a dose of only 0.4 mg will, within a few minutes, arouse a comatose person suffering from an opiate overdose; and a dose of 0.2 mg reversed analgesia produced by electrical stimulation in the human brain' (8).…”

Section: Discussionmentioning

confidence: 99%

Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects.

Grevert¹,

Goldstein²

1977

Proc. Natl. Acad. Sci. U.S.A.

129

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The hypothesis that painful stimuli activate the endogenous opioid (endorphin) system in humans was tested by examining the effect of the opiate antagonist naloxone on experimentally induced ischemic pain and on subjective mood ratings. Intravenous injections of saline or naloxone hydrochloride (2 and 10 mg) were administered under double-blind conditions to 12 subjects. Naloxone did not affect the pain ratings. However, a significant dose-related effect of naloxone on tension-anxiety was found, suggesting that the endorphins, like exogenously administered opiates, may have antianxiety properties.The discovery of endogenous substances with opioid activity (endorphins) in several species, including man (1-6), raises questions about what role these substances normally play. Since narcotic antagonists block and reverse the effects of opiates, the administration of these antagonists should similarly affect behavior mediated by endorphins. However, when administered to animals or humans who have not received an opiate, the "pure" antagonists, naloxone and naltrexone, appear to have no effect, suggesting that the endorphin system is not continuously active, but only activated in certain internal or environmental conditions. In both rats (7) and humans (8) naloxone diminishes analgesia produced by electric brain stimulation; however, it does not modify hypnotic analgesia in man (9). Naloxone does not alter threshold for escape from a noxious stimulus in trained rats (10), but it reduces the latency for escape behavior when mice or rats are exposed to a noxious stimulus for the first time (11, *).The purpose of the present study was to determine if painful stimuli activate the endorphin system in humans by examining the effect of naloxone on experimentally induced ischemic pain. In addition, recognizing the affective changes that result from administration of exogenous opiates, we hypothesized that naloxone would accentuate the stressful nature of the pain, resulting in a greater increase in anxiety, hostility, and depression than in the same situation without naloxone. METHODS Subjects. The subjects were six male and six female staff members who volunteered to participate in the study. The median age was 28 years. Informed consent was obtained.Drugs. Naloxone hydrochloride was dissolved in 0.9% saline solution at 2 and 10 mg/ml. At each session an intravenous injection of 1 ml of one of these solutions or of saline alone was administered at the rate of 1 ml/min. The sequence of drug administration was counterbalanced with the restriction that, as a precautionary measure, the 10 mg dose of naloxone was never administered first. Therefore, subjects were randomly assigned to one of the following sequences: saline, 2 mg naloxone, 10 mg paloxone; saline, 10 mg naloxone, 2 mg naloxone; 2 mg naloxone, saline, 10 mg naloxone; 2 mg naloxone, 10 mg naloxone, saline. Solutions were contained in identical vials coded by two-digit random numbers. They were prepared by a person who had no contact with the experiment. The exp...

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Section: Discussionmentioning

confidence: 99%

Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects.

Grevert¹,

Goldstein²

1977

Proc. Natl. Acad. Sci. U.S.A.

129

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“…Several observations suggest a common element in these approaches for pain relief. For instance, narcotic antagonists, such as naloxone (13), block analgesia induced by electrical stimulation (6)(7)(8)(9)14) and by morphine injections (15). Furthermore, tolerance develops to electrostimulation analgesia and to morphine analgesia and cross tolerance can be observed (16).…”

mentioning

confidence: 99%

Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkephalin and substance P.

Hökfelt¹,

Ljungdahl²,

Terenius³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

604

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The distribution of Met-enkephalin-and substance P-immunoreactive neurons was studied by indirect immunofluorescence in some areas related to pain and analgesia. Met-enkephalin-and substance P-positive cell bodies and nerve terminals were observed in the periaqueductal central gray, the nucleus raphe magnus, the marginal layer and substantia gelatinosa ofthe spinal trigeminal nucleus, and the dorsal horn of the spinal cord. Lesion experiments suggest that Met-enkephalin neurons in the dorsal horn and possibly in the spinal trigeminal nucleus are interneurons or propriospinal neurons with nerve terminals in the laminae I and II of tfe cord and in the superficial layers of the spinal trigeminal nucleus, respectively. These areas are also very rich in substance P-positive nerve terminals, mainly representing central branches of primary afferent neurons.The present immunohistochemical-anatomical findings support the hypothesis that stimulation-produced analgesia is related to activation of spinal and spinal trigeminal enkephalin interneurons forming axo-axonic synapses with (substance P?) pain afferents in the superficial laminae of the dorsal horn and the spinal trigeminal nucleus. These interneurons may be activated by sensory fibers and by descending fibers from medullary stimulation sites. Transmitter substances in these descending fibers may be 5-hydroxytryptamine and substance P. Morphine is a classical agent for the relief of severe, chronic pain. Strong analgesia can also be produced by electric stimulation of mesencephalic and medullary structures (refs. 1-9, see ref. 10), by acupuncture, or by "electroacupuncture" (11, 12), a modification of the classical Chinese procedure. Several observations suggest a common element in these approaches for pain relief. For instance, narcotic antagonists, such as naloxone (13), block analgesia induced by electrical stimulation (6)(7)(8)(9)14) and by morphine injections (15). Furthermore, tolerance develops to electrostimulation analgesia and to morphine analgesia and cross tolerance can be observed (16).Recently, Hughes and collaborators (17) have identified two pentapeptides, Leu-enkephalin and Met-enkephalin, that may represent endogenous ligands for opiate receptors. Available evidence suggests that the activity profile of endogenous opioids is similar to that of the opiates. For instance, enkephalin has analgesic activity in vivo and the narcotic antagonist naloxone will also counteract enkephalin-induced elevation of pain thresholds (18,19). It is therefore conceivable that these ligands may be involved in stimulation-produced analgesia.Using the immunohistochemical approach, we have been able to outline the gross distribution of enkephalin-positive structures in the central nervous system (refs. 20 and 21, see also ref. 22). Enkephalin neurons were found in many areas of the brain and spinal cord, indicating involvement in many different types of central nervous system functions. Here, however, we focus attention strictly on areas assumed to be of importa...

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“…Also, animal experiments have shown that electrical stimulation or electrodes implanted in the brainstem cause release of endorphins and enkephlin-like material into the cerebrospinal fluid which, in turn, produces analgesia [49]. In 1976, Adams [50] discovered that the analgesia produced by brain stimulation could be reversed by giving naloxone. An additional explanation for the analgesia produced by electrical stimulation was offered by Melzack, who suggested the existence of a powerful descending inhibitory system in the region of the periaqueductal gray matter of the aqueduct of Sylvius.…”

Section: Transcutaneous Electrical Nerve Stimulationmentioning

confidence: 99%

Postoperative Pain Management: An Anesthesiologists'Opportunity and Challenge

Sami

1991

Ann Saudi Med

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Naloxone reversal of analgesia produced by brain stimulation in the human

Cited by 251 publications

References 7 publications

Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects.

Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects.

Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkephalin and substance P.

Postoperative Pain Management: An Anesthesiologists'Opportunity and Challenge

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