Sex is one of biology's, that is, life's most potent experimental variables. So, are there sex differences in pain? And are these sex differences applicable clinically? The answer to both questions is decidedly yes, of course. But we still have a long way to go. We have much to learn from the study of females, making use of the lifelong changes in their reproductive conditions as experimental variables. We also have much to learn from animals, especially if we apply what we know about their social lives. However, the challenge in all of these studies is not first to look for some mythical neurological entity called pain experience and then to learn how sex modulates it, but rather to seek to understand the rules by which sex influences all of biology's mutually modulatory factors – social, psychological, physiological, cellular, molecular, and genetic – that collectively create the motivating circumstances we designate as pain. It appears almost beyond doubt that on the one hand these factors interact to make women more vulnerable to these circumstances than men, but on the other hand that women have more varied mechanisms for balance. Happily, the details of these sex differences at all levels biological (social to genetic) are now emerging in a rapidly growing body of literature that promises new insights into and applications for the individual person, male or female, in persistent pain.

It is suggested that bifurcation of parallel fibres in the cerebellar cortex assists the spatiotemporal convergence of temporally dispersed and asomatotopic inputs to granule cells. This increases the number of combinations of inputs which can be compared for the purpose of sequence recognition.

Controversy surrounds several experiments that have addressed whether selective synaptic strengthening occurs during learning. To date, the evidence suggests that widespread alterations in synaptic strength, through either kindling or electroconvulsive shock, can disrupt this hypothetical process. The lack of evidence for selective modification of learning through LTP stimulation, however, provides difficulties for both the prevailing hypothesis and the hypothesis advanced by Shors & Matzel. Subsequent experiments may indicate a role for LTP in both learning and arousal.

Biological neural computation relies a great deal on architecture, which constrains the types of content that can be processed by distinct modules in the brain. Though artificial neural networks are useful tools and give insight, they cannot be relied upon yet to give definitive answers to problems in cognition. Knowledge re-use may be driven more by architectural inheritance than by epistemological drives.

Although Clark & Thornton's “trading spaces” hypothesis is supposed to require trading internal representation for computation, it is not used consistently in that fashion. Not only do some of the offered computation-saving strategies turn out to be nonrepresentational, others (e.g., cultural artifacts) are external representations. Hence, C&T's hypothesis is consistent with antirepresentationalism.

The “sequence-in/sequence-out” model of cerebellar operation is mostly speculation. The same data can be interpreted in a very different way, making fewer assumptions. To wit, sets of Purkinje cells recognize a specific sensorimotor event and trigger a synchronous sensorimotor discharge.

In this response, I discuss the roles of the peripheral afferent drive in the maintenance of persistent pain, the concept of pre-emptive analgesia and the importance of the brain, the detailed involvement of which in pain is far less well understood compared to the events in the spinal cord. A comparison of pain to other sensory modalities is then made together with a discussion of learning and pain. These facets of pain are discussed in the light of treatment strategies for this condition.

Recent evidence from our lab indicates that LTP shares an important property with memory consolidation: it is consolidated by natural reinforcement. Nevertheless, the hypothesis, that LTP-like mechanisms or other forms of enhanced synaptic efficacy are basic elements in learning is not unequivocally supported. Skepticism aside, LTP is an accessible experimental model that is optimally equipped for the investigation of the cellular and molecular machinery involved in synaptic weight changes.

Just as physics determines physically viable movements, the spatial distribution of input excitations allows the cerebellum to choose physiologically viable beams. Cerebellar–motor coherence implies that the ordering and modes of combination of cerebellar beams reflect (1) the way movement invariants are ordered and combined in movement and (2) the way physical principles are integrated in learning to move.

Shors & Matzel's conclusion that LTP is not related to learning is similar to one we reached several years ago. We discuss some methodological advances that have relevance to the issue and applaud the authors for challenging existing dogma.

The commentaries on our target article have raised important issues about central neuroplasticity and its role in persistent pain states. Some suggest that central neuroplasticity plays nothing more than a minor role in persistent pain, while others argue that persistent pain depends critically on peripheral inputs for its maintenance. Some stress that persistent pain relies to a large extent on changes in the brain and on centrifugal inputs from brain to spinal cord, whereas others argue that it depends on alterations in inhibitory as well as excitatory systems. We attempt to address each of the commentators' points, while defending our position that central neuroplasticity is critical to pathological persistent pain states.

Clark & Thornton's conception finds an echo in implicit learning research, which shows that subjects may perform adaptively in complex structured situations through the use of simple statistical learning mechanisms. However, the authors fail to draw a distinction between, on the one hand, subjects' representations which emerge from type-1 learning mechanisms, and, on the other, their knowledge of the genuine abstract “recoding function” which defines a type-2 problem.

(1) The “timing idea” is not the only interpretation of cerebellar histology worth considering. Therefore, it is not imperative to strive for a theory of cerebellar function which gives it a prominent rôle. (2) The experiments with “moving stimuli” cannot support the tidal wave theory. (3) The notion that only “moving stimuli” can excite the cerebellar cortex is burdened with many intrinsic difficulties. (4) The common theoretical claim that the accuracy of skilled movements is due to exact pattern-matching processes in the cerebellum may be most misleading.

The theme of my target article was dysfunction of inhibition in the spinal cord as an important factor in the development of chronic pain states. Some commentaries focused on the role of more central mechanisms and the limited usefulness of animal models for understanding mechanisms of human pain. More specific comments concerned the roles of GABA and cholecystokinin in pain control.

Clark & Thornton present the well-established principle that recoding inputs can make learning easier. A useful goal would be to make such recoding automatic. We discuss some ways in which incrementality and transfer in connectionist networks could attain this goal.

Shors & Matzel propose that hippocampal LTP increases the effective salience of discrete external stimuli and thereby facilitates the induction of memories at distant places. In line with this suggestion, a neural network model of associative learning and hippocampal function assumes that LTP increases hippocampal error signals to the cortex, thereby facilitating stimulus configuration in association cortex. Computer simulations show that under these assumptions the model correctly describes the effect of LTP induction and blockade in classical discriminations and place learning.

Mormyrid teleosts have Purkinje cells with palisade dendrites, which probably represent coincidence detectors of parallel fiber activity. Their existence strongly supports the ideas of Braitenberg et al. on cerebellar function. However, the organization of mormyrid granule cells and parallel fibers suggests that a key to cerebellar function is not in interactions within one wave, but between two opposite tidal waves.

Certain patients with a possible contribution of the sympathetic system to pain may not fit the definition of complex regional pain syndromes (CRPS), which raises the question of terminology for those patients. To further clarify the relationship between the sympathetic system and pain, apart from the need for placebo studies, there remains an urgent need for a satisfactory definition of the criteria for a complete sympathetic block. It also remains uncertain whether a change in the discharge pattern of sympathetic fibres underlies the changes in sympathetic organ function, often found in patients with CRPS.

We argue that existing learning algorithms are often poorly equipped to solve problems involving a certain type of important and widespread regularity that we call “type-2 regularity.” The solution in these cases is to trade achieved representation against computational search. We investigate several ways in which such a trade-off may be pursued including simple incremental learning, modular connectionism, and the developmental hypothesis of “representational redescription.”

Shors & Matzel set up a straw man, that LTP is a memory storage mechanism, and knock him down without due consideration of the important relations among different levels of organization and analysis regarding LTP, learning, and memory. Assessing these relationships requires analysis and hypotheses linking specific brain regions, neural circuits, plasticity mechanisms, and task demands. The issue addressed by the authors is important, but their analysis is off target.