Pleasure in pursuit of answers

Reply Pleasure in Pursuit of Answers Karen J. Berkley hat indeed is the "significance" of viscerosomatic convergence? It is clear from the four commentaries (and the comments of four anonymous reviewers) that there are multiple potential and compatible answers to this satisfyingly challenging question. W SPECIFICITY OF FUNCTIONAL ORGANIZATION Albe-Fessard reviews substantive classical neurophysiological data, much of it preceding Chernigovskiy's 1967 review book. 8 She concludes that a greater degree of specific functional organization exists among the several somatic pathways that concomitantly code visceral and somatic information than was implied in the focus article. Cervero reviews much of his own, more recent, seminal data to conclude nearly the same thing, although he argues for even more specificity than does Albe-Fessard. Two anonymous reviewers made similar statements. It is undeniable that viscerosomatic convergence is more selective than random or universal. Not all neurons responsive to somatic stimuli are found to be responsive to visceral stimuli, and vice versa. Like Cervero and others studying neurons in the spinal cord, Gis~le Guilbaud and 14saw this kind of specificity in neuronal responsiveness when we recorded responses of neurons to reproductive organ and somatic stimuli in different parts of the thalamus in and near the ventrobasal complex of female rats. Ventrobasal complex somatic-responsive neurons were less likely to respond to our pelvic visceral stimuli than were neurons surrounding the ventrobasal complex. From the Program in Neuroscience, Department of Psychology, Florida State University,Taliahassee, FL. Reprint requests: Dr. Karen J. Berkley, Program in Neuroscience, Department of Psychology, Florida State University,Tallahassee, FL 32306-1051. 262 In addition, as reviewed in the focus article and shown more recently in Card et al., 5 there is clear evidence for the existence of highly organized "visceral neuroaxes" located outside the classical somatic pathways, some of whose neurons have proven impossible to activate by natural or electrical cutaneous somatic stimuli, a,9 Furthermore, inhibitory mechanisms exist that can carve a certain specificity from convergence (as discussed by one reviewer, by Chernigovskiy, and briefly by Randich, when referencing the elegant work of Foreman's group, 7 and as observed by us15). What is becoming more and more evident is that convergence is a more prevalent or inducible characteristic of neurons throughout the entire nervous system than one would have believed or would like to believe. Although Cervero and Guilbaud and I point out that certain spinal or ventrobasal complex neurons, respectively, failed in our studies to respond to the visceral stimuli we applied, our results do not preclude responses of those neurons to other visceral stimuli, such as the cardiovascular, esophageal, colonic, and bladder stimuli used by others (and reviewed in the references cited in the focus article). Similarly, even within presumably pure visceral regions such as the solitary nucleus, neurons can be activated by strong electrical stimulation of cutaneous and muscle nervesY Finally, and most important, as pointed out by Wall, convergence characteristics are subject to considerable, sometimes dramatic change--likely due to changes in the balance of excitatory and inhibitory mechanisms (including the ones mentioned above and discussed by Albe-Fessard)--under varying biological and pathological conditions, and thus by extension under different, many as yet untried, experimental conditions. The existence of so many neurons throughout the neuroaxis that are capable of being induced into being responsive to both somatic and visceral stimuli forces us to admit the possibility that single neurons are capable of being involved in multiple functions. APS Journal 2(4): 262-264, 1993 REPLY/Berkley The problem is not whether a specific functional organization exists, which under a very constant set of biological circumstances seems highly likely, but rather, figuring out ways to improve our understanding of how the nervous system manipulates those capabilities under different circumstances to produce various functional organizations (as represented abstractly in Fig. 2B of the focus article) and behavioral coherence. CRACKING THE CODE It is obvious that this is not an easy task. As suggested by Randich, it may be helpful to define "viscerosomatic convergence" more rigorously, in part by distinguishing neurons that receive convergence anatomically (viscerosomatic convergence) from those that respond to both visceral and somatic stimulation but do not receive direct anatomical convergence (viscerosomatic system interactions). While thoughtfully articulated, this semantic distinction is problematic for many reasons. First, anatomical convergence is only as good as the sensitivity of the methods being used and, thus, is subject to continual change, usually increased estimates. Second, what do we do about neurons up-the-line from those with and without anatomical convergence? Third, what about other sources of relatively direct convergence (e.g., release of neuroactive molecules into extracellular space)? Fourth and finally, how do we deal with neurons whose electrophysiological convergence characteristics are subject to the dramatic changes discussed above? In the long run, it may simply be more practical to continue using the term viscerosomatic convergence in the general way it has been used, that is, as a descriptor for any neuron subject to influence from visceral and somatic sources, and then ask, as Randich does so carefully in his examples, a series of logical questions about the effects of and basis for this influence. In fact, the examples Randich used to illustrate his dilemma in "choosing which neurons to study" actually provide an illustration of a productive way to proceed. Returning to the original conclusion that the surprising prevalence of inducible viscerosomatic convergence forces admission of the possibility that single neurons are capable of being involved in multiple functions, it becomes important to recognize that admitting that single neurons can be involved in more than one function is not the same as saying that those neurons have more than one function. Such an admission does say that understanding the neurons' function(s) requires consideration of their responses in the context of what else 263 has happened to the animal and what else is happening to the animal concurrently in the nervous system and in the animal's environment. Thus, as Wall indicates, a productive strategy is to work backward from the response or, better, to "correlate the signal with its results." Accordingly, what was clearly helpful to Randich in interpreting the responses of the rostral ventromedial medulla neuron he describes was his prior understanding of the rostral ventromedial medulla neuron's involvement in cardiovascular regulation. Conversely, what made it more difficult for him to interpret the responses of the spinal T5 neuron he describes was a lack of such an understanding. PURPOSES OF CONVERGENCE Randich correctly understood, and stated in a much more animated way than I did, that one point of the focus article was to suggest that viscerosomatic convergence may indicate that visceral systems probably borrow cutaneous-motor systems when their own peripheral protective mechanisms fail and that one of many possible results of this tactic would be referred pain. This hypothesis is, as he and Wall indicate, testable, but, as Albe-Fessard points out, it may not explain all things (such as referred hyperalgesia) and thus probably needs further elaboration. Wall pointed out how investigators in other areas of neuroscience have interpreted the purposes of convergence in their own realms. It is evident from his scholarly and valuable discussion that convergence, like inhibition, represents a general neural mechanism useful in many realms of neural function and that appreciating these other uses can be valuable for improving our own understanding of pain mechanisms. LOOKING TOWARD THE FUTURE While one objective of the focus article was to provide a specific hypothesis about one possible consequence of viscerosomatic convergence, another more important objective was to use the surprisingly high actual and potential prevalence of viscerosomatic convergent neurons to present an attitude about nervous system function (Fig. 2) that would encourage us to develop alternative ways of interpreting experimental results. The point is that more of us should pay more than lip service to the incredible dynamics of nervous system organization. We should adopt the premise that the function(s) of a given neuron or group of neurons depend on the context (current and past) in which they are currently active and the overall activity in the rest of the ner- 264 REPLY/Berkley vous system. Once we really do that, our experiments and the ways we interpret their results ought to move in more productive directions. For one, physiological experiments would more likely be performed in ways that permit us to associate neural responses with behavior. This could range from simply focusing more attention on the biological conditions of the animals we study (such as time of day, sex, age, prior surgical and social history, etc.) and how such conditions might affect our data, 3 to more experiments in which we study neuronal responses in awake, responding animals under different biological conditions (e.g., 2):, to more experiments in which we study neurons in different systems simultaneously (e.g., 1,1o.14). Other experiments would be geared toward gaining a better understanding of the processes that link neural systems together. As discussed by Wall and mentioned in the focus article, exciting investigations are underway in other realms of neuroscience (from which we should take clues) where creative attempts are being made to understand the electrophysiological bases of these linkage processes, perhaps through some type of time synchronization. Investigations are also underway to try to understand how systems might be linked via highly malleable slower chemical or electrochemical transfer proc e s s e s . 5.11,12 It is evident and unfortunate that cracking the code, as Wall succinctly puts it, is a goal we are not likely to achieve in our lifetime, if ever. But such pessimism does not preclude our approaching that elusive goal in small steps. Indeed, as I see it, it is just this deliciously frustrating approach that provides so many of the satisfactions and pleasures in what we do as scientists, posing, one at a time, discrete biological questions whose answers relate to bigger biological problems but simultaneously give rise to yet more discrete biological questions. Who knows, but perhaps as pain scientists and clinicians we may someday begin studying more vigorously a topic that is clearly relevant to our field but has been woefully neglected: the neural mechanisms of pleasure. References 1. Apkarian AV, Stea RA, Manglos SH et al: Persistent pain inhibits contralateral somatosensory cortical activity in humans. Neurosci Lett 140:141-147, 1992 2. Belczynski CR Jr, Pertovaara A, Morrow TJ, Casey KL: The effect of systemic cocaine on the responses to noxious stimuli and spontaneous activity of medial bulboreticular projection neurons. Brain Res 527: 204-212, 1990 3. Berkley KJ: Sex and chronobiology: opportunities for a focus on the positive, pp. 2-5. IASP Newsletter Jan/ Feb 1993 4. Berkley KJ, Guilbaud G, Benoist J-M, Gautron M: Responses of neurons in and near the ventrobasal complex of the rat to stimulation of uterus, cervix, vagina, colon, and skin. J Neurophysiol 69:557-568, 1993 5. Card JP, Rinaman L, Lynn RB et al: Pseudorabies virus infection of the rat central nervous system: ultrastructural characterization of viral replication, transport, and pathogenesis. J Neurosci 13:2515-2539, 1993 6. Chernigovskiy VN, Onischenko G, trans. Interoceptors. American Psychological Assoc, Washington, DC, 1967 7. Foreman RD, Hobbs SF, Uh-Taek O, Chandler MJ: Differential modulation of thoracic and lumbar spinothalamic tract cell activity during stimulation of cardiopulmonary sympathetic afferent fibers in the primate: a new concept for visceral pain? pp. 227-231. In Dubner R, Gebhart GF, Bonds MR (eds): Proceedings of the Fifth World Congress on Pain. Elsevier Science, Amsterdam, 1988 8. HenryJL, Sessle BJ: Vasopressin and oxytocin express excitatory effects on respiratory and respiration-related neurones in the nuclei of the tractus solitarius in the cat. Brain Res 491:150-155, 1989 9. Hubscher CH, Berkley KJ: Neuronal responses to stimulation of uterus, cervix, vaginal canal and colon in the rat solitary nucleus. Soc Neurosci Abstr 19:514, 1993 10. Jones AKPI Brown WDC, Friston KJ et al: Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc R Soc Lond (Biol) 244:39-44, 1991 11. Lewin GR, Winter J, McMahon SB: Regulation of afferent connectivity in the adult spinal cord by nerve growth factor. Eur J Neurosci 4:700-707, 1992 12. Mercer JG, Lawrence CB, Copeland PA: Corticotropinreleasing factor binding sites undergo axonal transport in the rat vagus nerve. J Neuroendocrinol 4: 281-285, 1992 13. Person RJ: Somatic and vagal afferent convergence on solitary tract neurons in cat: electrophysiological characteristics. Neuroscience 30:283-295, 1989 14. Talbot JD, Marrett S, Evans AC et al: Multiple representations of pain in human cerebral cortex. Science 251 : 1355-1358, 1991 15. Wall PD, Hubscher CH, Berkley KJ: Intraspinal modulation of neuronal responses to uterine and cervix stimulation in rat L1 and L6 dorsal horn. Brain Res 1993 (in press)