Neurotransmitters in Nociceptive Modulatory Circuits

Abstract

Significant advances have been made in our understanding of nociceptive modulation from RVM. Among the most useful conceptually has been the discovery that there are two classes of modulatory neurons in the RVM that are likely to have opposing actions on nociception: on-cells, which may facilitate nociceptive transmission, and off-cells, which probably have a net inhibitory effect on nociception. The similarity in response properties among the members of each class, their large, somatic "receptive fields," and the wide distribution of the terminal fields of axons of individual neurons to the trigeminal sensory complex and to multiple spinal segments indicate that these neurons exert a global influence over nociceptive responsiveness. Drug microinjections into the RVM presumably shift the balance between states of on- or off-cell firing and also produce measurable changes in the threshold for nocifensor reflexes. The meaningful unit of function in the RVM nociceptive modulatory system therefore probably consists of large ensembles of physiologically and pharmacologically similar neurons. The strong coordination of activity of the two classes of RVM neuron may depend largely upon intranuclear projections from RVM off-cells that excite other off-cells and inhibit on-cells. The off-cell pause is GABA-mediated, and it is likely that there is a subset of GABA-containing RVM on-cells that directly inhibit off-cells. Furthermore, the available evidence indicates that exogenous opiates activate off-cells by inhibiting GABAergic release. Presumably, enkephalinergic cells in the RVM disinhibit off-cells in a similar way. Although non-serotonin-containing off-cells certainly exist, we propose that some off-cells contain serotonin. Other possible connections are based on more limited data; however, ACh, neurotensin, NE, and EAAs are present in neurons that project to the RVM, and each of these compounds, when microinjected into the RVM, has a modulating effect on nociceptive transmission. The local circuits in the RVM that underlie these actions remain to be elucidated. At the level of the dorsal horn, there is good evidence for each of three inhibitory mechanisms: direct inhibition of nociceptive projection neurons, inhibition of excitatory relay interneurons, and excitation of an inhibitory interneuron. The relative contribution made by each of these circuits is unknown.(ABSTRACT TRUNCATED AT 400 WORDS)

Hyperalgesic effect induced by barbiturates, midazolam and ethanol: pharmacological evidence for GABA-A receptor involvement

“…Barbiturates, benzodiazepines and ethanol are known to be agonists of the GABA-A receptor complex which are ubiquitously distributed throughout the CNS, including the descendent inhibitory system (7,21). A biturates in the dose range used (data not shown).…”

Discharge of Raphe Magnus on and offCells Is Predictive of the Motor Facilitation Evoked by Repeated Laser Stimulation

“…ON and OFF cells have the appropriate physiology to mediate the motor facilitation that is observed to repeated stimulation. OFF cells are excited by analgesic doses of opioids and are likely to act as the nociceptiveinhibitory output neuron of RM (Basbaum and Fields, 1984;Fields et al, 1991;Porreca et al, 2002). In contrast, ON cells are excited by peripheral noxious stimulation, inhibited by opioids, and have recently been implicated as critical mediators of nociceptive reactions (Porreca et al, 2002).…”

Effects of pedunculopontine tegmental nucleus lesions on morphine-induced conditioned place preference and analgesia in the formalin test

“…The evidence outlined above indicates that analgesia in the formalin test is not mediated through the system outlined by Fields (1991). Rather, forebrain structures appear to be responsible for t~e effect because lesions of the median raphe, which projects rostrally to forebrain structures (Conrad et al, 1974), have no effect on thü tail flick test Melzack, 1982: Buxbaum et al, 1973), but potentiate morphine analgesia in the formalin test (Abbott and Melzack, 1982).…”