Trends in Neurosciences. Inhibitory influences arising from the brain that descend in the spinal cord to modulate spinal reflexes. The PAG receives projections from a number of brain regions, including the amygdala, frontal and insular cortex, and hypothalamus, and acts in concert with the rostral ventromedial medulla RVM to provide a descending pain modulatory system. In addition to direct neural connections, endorphins synthesized in the pituitary are released into the cerebrospinal fluid and blood, where they can exert an inhibitory effect at several centers, including the PAG.
Descending inhibition may be activated by external factors such as stress stressinduced analgesia and noxious input diffuse noxious inhibitory controls , or can be induced by peripheral or central nervous stimulation.
Physiology of pain. Foundations of Anesthesia. London, UK: Mosby; On and off cells in the RVM cells respond to manipulations of the periaqueductal gray PAG to produce behavioral analgesia by exerting a net inhibitory effect on nociception. Central nervous system mechanisms of pain modulation. Opioid receptors are distributed throughout the pain-modulating circuit and exert a modulatory effect on nociceptive input.
The release of endogenous opioid ligands at spinal sites can produce an analgesic effect. These substances function in part by reducing transmitter release from the dorsal horn terminals of primary afferent nociceptors. They also direct postsynaptic inhibition of central neurons that are activated by noxious stimulation. Endogenous opioids also contribute to pain modulation by inhibiting neuropeptide release from primary afferents.
While PAG stimulation has been largely discontinued because of side effects, such as anxiety, distress, and, in some instances, development of migraine-like headache 20 , deep brain stimulation aimed at other regions remains an approach that might control otherwise intractable pain Critically, the reversal of intractable pain by stimulation of the PAG was blocked by naloxone, indicating the activation of an endogenous opioidergic pain inhibitory system These early studies were not rigorous, placebo-controlled double-blind trials, and, as a consequence, the possibility of placebo analgesia cannot be disregarded.
Even so, the existence of a placebo effect, as discussed above, is likely dependent on activation of pain modulatory circuits. Preclinical studies have attempted to delineate the sites and pathways that compose the endogenous pain inhibitory circuit. Considerable overlap has been found between sites that produce antinociception with either electrical stimulation or morphine microinjection 22 — Both stimulation-produced antinociception SPA and antinociception from morphine microinjection into supraspinal loci are reversed by naloxone, further implicating the activation of endogenous opioidergic systems in these phenomena These studies have revealed descending pain inhibitory projections to the level of the spinal cord, either directly or indirectly from the PAG.
Surgical disruption of the dorsolateral funiculus DLF abolished supraspinally mediated antinociception 26 , and anterograde and retrograde tracing studies revealed that the RVM sends spinopetal projections through this tract 28 — The precise site of projection of these fibers and their role in inhibition or facilitation remains unclear.
Human imaging studies reveal connections linking the PAG to the amygdala and cortical sites 2 , The amygdala plays important roles in emotional responses, stress, and anxiety and is believed to be a critical component of the pain matrix. This region may contribute significantly to the integration of pain and associated responses such as fear and anxiety.
Electrophysiological studies in animals demonstrated that neurons of the central nucleus of the amygdala CeA showed excitation with noxious stimulation of the knee joint or deep tissue 33 and enhanced responses after peripheral 34 or visceral 35 inflammation.
Sensitization of CeA neurons, mediated through metabotropic glutamate receptors, represents neuroplastic changes that appear to promote chronic pain 36 , Administration of a corticotropin-releasing factor CRF1 receptor antagonist into the CeA of rats inhibited both nociceptive responses as well as anxiety-like behaviors Hemispheric lateralization of the role of the amygdala in pain processing has been recently demonstrated, since, although both the left and right CeA showed responses to brief noxious stimuli, only the right CeA responded with enhancement of firing and increased receptive field size after either ipsilateral or contralateral peripheral inflammation Moreover, peripheral inflammation produced activation of extracellular signal-regulated kinase cascade only in the right CeA, regardless of site of inflammation 40 , and blockade of activity of this kinase in the right CeA, but not the left CeA, blocked behavioral signs of enhanced inflammatory pain Electrophysiologic studies and lesioning experiments have revealed that the RVM receives neuronal inputs from the PAG and is likely to be the final common relay in descending inhibition of nociception from supraspinal sites The microinjection of lidocaine into the RVM abolished antinociception arising from electrical stimulation of the PAG Descending projections from the RVM course through the DLF to the spinal dorsal horn and form synaptic connections with primary afferent terminals and second- and third-order neurons that transmit nociceptive signals to supraspinal sites as well as with interneurons and thus are well situated to modulate nociceptive inputs 43 — Important insights into the nature of descending modulatory circuitry came from studies by Fields and colleagues, in which activity of neurons in the RVM were paired with a behavior elicited by a noxious stimulus i.
These studies led to the identification of a population of RVM neurons that increase firing just prior to the initiation of the nociceptive reflex i. Both the off-cells and on-cells were found to project to the spinal dorsal horn, indicating that they may exert modulatory influences on nociceptive inputs 51 — This dichotomy in neuronal function is consistent with bidirectional pain modulation.
Studies performed with electrical stimulation or microinjection of glutamate into the RVM revealed a biphasic function of the RVM, with regard to pain modulation 53 — Low intensities of stimulation inhibited nociceptive responses, whereas higher levels of stimulation enhanced nociception 53 — This biphasic role of the RVM in pain modulation was shown with electrophysiologic responses of spinal cord neurons or with behavioral responses and occurred with either cutaneous or visceral stimuli 53 — The electrophysiologic characteristics of the on-cells are consistent with a pronociceptive function.
For example, prolonged delivery of a noxious thermal stimulus increased the firing rate of RVM on-cells as well as enhanced the intensity of the nociceptive response in rats Both enhanced nociceptive responses and increased on-cell activity were abolished by lidocaine microinjected into the RVM Hyperalgesia caused by naloxone-precipitated withdrawal was accompanied by increased on-cell activity Finally, the subdermal injection of formalin into a hind paw of a rat produced exaggerated behavioral responses as well as increased responses of on-cells of the RVM The activation of descending inhibitory pathways that project to the spinal and medullary dorsal horns has led to the question of the nature of these projections.
Additionally, most i. However, the role of GABA in the function of these cells remains unclear. Early studies with available serotonergic antagonists blocked SPA initiated from the RVM 68 , leading to the suggestion that descending inhibition of pain was mediated through serotonergic neurons projecting from the RVM through the DLF Retrograde labeling studies demonstrated the presence of serotonergic projections to the spinal dorsal horn arising from the nucleus raphe magnus, which is a midline structure within the RVM as well as the nucleus paragigantocellularis and the ventral portion of the nucleus gigantocellularis Together, such studies led to the reasonable assumption that the RVM provided descending serotonergic pain modulation from the RVM.
However, attempts to determine whether either the on-cells or off-cells of the RVM are serotonergic led to the realization that other, nonserotonergic neurons from the RVM may modulate pain In a study of 25 identified RVM neurons, none of the on-cells i. It has been argued that serotonergic RVM neurons are neither on-cells nor off-cells but that they can modulate the activities of these neurons see refs. However, a recent study, in which descending serotonergic RVM neurons were selectively ablated through the use of shRNA plasmids and electroporation, demonstrated that descending serotonergic projections from the RVM are important for facilitation of pain in inflammatory or neuropathic pain states, although they are not necessary for opioid-mediated inhibition of acute pain In addition to the descending serotonergic populations that are activated, the diversity of subtypes of the 5-HT receptors and the complex anatomy of the spinal dorsal horn complicates interpretation of the role of serotonin in pain modulation.
The effect of spinal serotonin can be either inhibitory or facilitatory, depending on the receptor subtype activated 78 — Spinal administration of an antagonist of the inhibitory 5-HT7 receptor blocked the antinociceptive effect of morphine microinjected into the RVM, whereas pharmacological antagonism of the facilitatory 5-HT3 receptor blocked hyperalgesia induced by CCK administered into the RVM Further, systemic administration of 5-HT7 agonists blocked capsaicin-induced hyperalgesia in mice, whereas 5-HT7 antagonists elicited mechanical hypersensitivity The 5-HT7 receptor has been identified in the dorsal root ganglion and on central terminals of primary afferent fibers 84 , 85 as well as on GABAergic interneurons in the dorsal horn of the spinal cord 84 , which is consistent with a role in pain modulation Although these observations indicate an important serotonergic role for pain modulation, the precise spinal mechanisms involved remain unclear.
Electrical stimulation of the PAG or RVM to elicit antinociception increases measured norepinephrine levels in the cerebrospinal fluid, and this effect was blocked by spinal adrenergic antagonists 69 , 86 — These findings suggest a strong contribution of norepinephrine in antinociception associated with descending inhibition.
These noradrenergic nuclei are a major source of direct noradrenergic projections to the spinal cord 3 , 92 and likely may serve to ultimately inhibit the response of presynaptic and postsynaptic spinal pain transmission neurons 3 , Spinal clonidine blocked thermal and capsaicin-induced pain in healthy human volunteers The mechanisms mediating the suppression of pain by stress have been intensively studied.
Watkins and colleagues 99 found that stress induced by brief foot shock of the forepaws of rats produced antinociception as measured in the tail-flick test. Lesions of the DLF made rostral to the entry zone of the peripheral nerves of the forelimbs, which kept intact any direct spinal communications between forelimb and tail, abolished stress-induced analgesia SIA , indicating that supraspinal sites were necessary to activate a spinopetal pain inhibitory circuit Additionally, it was found that antinociception induced by brief shock of the forepaws was abolished by systemic and intrathecal naloxone, indicating the activation of endogenous opioidergic pain inhibitory systems Stress induced by foot shock reduced firing of RVM on-cells and increased that of off-cells, consistent with opioidergic endogenous pain modulatory systems Opioid microinjection into the amygdala elicits antinociception that is blocked by lidocaine in either the PAG or RVM These and other studies led to the conclusion that SIA can be opioid sensitive and mediated through descending inhibitory pathways from amygdala, the PAG, and through RVM projections to the spinal cord However, preclinical studies have also revealed that some aspects of SIA are not sensitive to naloxone and therefore are likely to be mediated via different mechanisms.
Recent studies have revealed a role of endogenous cannabinoids in SIA and in descending modulatory pathways. Inhibition of RVM activity by microinjection of muscimol abolished antinociception induced by systemic injection of the cannabinoid agonist WIN55, It has been suggested that endogenous opiates are released in response to stress and inhibit pain by activating the midbrain descending system.
Moreover, some SIA exhibited cross tolerance with opiate analgesia, which indicates that this SIA is mediated via opiate receptors. Experiments using different parameters of electrical shock stimulation demonstrate that such stress produces analgesia and some of these stresses that produce analgesia could be blocked by the opioid antagonist naloxone, whereas others were not blocked by naloxone. These observations lead to the conclusion that both opiate and non-opiate forms of SIA exist.
The modulation of pain by electrical brain stimulation results from the activation of descending inhibitory fibers, which modulate block the input and output of laminae I, II, V and VII neurons. The route from the PAG to the spinal cord is not direct. Opioid and serotonergic antagonists reverse both local opiate analgesia and brain-stimulation produced analgesia. In conclusion, in the CNS, much of the information from the nociceptive afferent fibers results from excitatory discharges of multireceptive neurons.
The pain information in the CNS is controlled by ascending and descending inhibitory systems, using endogenous opioids, or other endogenous substances like serotonin as inhibitory mediators.
In addition, a powerful inhibition of pain-related information occurs in the spinal cord. These inhibitory systems can be activated by brain stimulation, intracerebral microinjection of morphine, and peripheral nerve stimulation. Centrally acting analgesic drugs activate these inhibitory control systems. However, pain is a complex perception that is influenced also by prior experience and by the context within which the noxious stimulus occurs.
This sensation is also influenced by emotional state. Therefore, the response to pain varies from subject to subject. Descending corticospinal fibers produce postsynaptic inhibition of nociceptive spinal neurons will not affect pain sensation. Descending spinothalamic fibers produce presynaptic inhibition of Rexed lamina VII neurons. The spinothalamic fibers are ascending fibers that carry pain information to the thalamus.
The descending dorsolateral fasciculus fibers suppress pain in the spinal cord. Pain stimuli activate descending fibers in the dorsolateral fasciculus. Transection of the dorsal column blocks the descending fibers producing analgesia. The dorsal column does not carry the descending dorsolateral fiber, therefore their transaction will not affect SPH. Ascending pain suppression system. Non-noxious input suppresses pain at the spinal cord.
Melzack and Wall assume that peripheral non-noxious stimulation will inhibit presynaptically the pain conducting pulses at the spinal cord target cells T cells and will prevent pain sensation from being transmitted to higher centers. Electrical simulation-produced analgesia. Cortical control system suppresses pain. Descending pain suppression system. Stimulation at the central gray and the Raphe nuclei produces analgesia via dorsolateral funiculus descendign fibers.
Opiate Analgesia OA The most effective clinically used drugs for producing temporary analgesia and relief from pain are the opioid family, which includes morphine, and heroin. Endogenous Opioids Opioidergic neurotransmission is found throughout the brain and spinal cord and appears to influence many CNS functions, including nociception, cardiovascular functions, thermoregulation, respiration, neuroendocrine functions, neuroimmune functions, food intake, sexual activity, aggressive locomotor behavior as well as learning and memory.
Gate Control theory The first pain modulatory mechanism called the " Gate Control " theory was proposed by Melzack and Wall in the mid s. According to the descending pain suppression theory, A. Mechanical stimulation produces presynaptic inhibition, not postsynaptic inhibition. Corticospinal fibers innervate motor neurons, and have no effect on nociceptive spinal neurons.
The Melzack-Wall gate theory refers to: A. Circular movement B. Analgesia C. Catatonia D. Tremors E. Electrical stimulation in the periaqueductal gray elicits: A. PAG stimulation causes the release of endorphins to the circulation which produce analgesia.
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