By Carl Y. Saab, Ph.D. Yale/VA
How painful is your pain?
When I volunteered for a pain study, an increasing pressure was applied on my finger by a simple weight-drop machine while researchers where acquiring fMRI scans of my brain ‘in action’ (or rather ‘in reaction’ to the painful stimulus). When the increasing pressure reached my pain threshold, I was asked to rate my pain on a scale of 1 to 10, with 10 being the most imaginable pain. I rated my pain back then as 7. A few weeks later I read the following in Discipline and Punish by M. Foucault (1995):
“On 2nd of March 1757, Damiens the regicide was condemned […] to be taken and conveyed in a cart, wearing nothing but a shirt, holding a torch of burning wax weighing two pounds, then, in the said cart, […] the flesh will be torn from his breasts, arms, thighs and calves with red-hot pincers, his right hand, holding the knife with which he committed the said parricide, burnt with sulphur, and, on those places where the flesh will be torn away, poured molten lead, boiling oil, burning resin, wax and sulphur melted together and then […] his limbs and body drawn and quartered by four horses and […] consumed by fire, reduced to ashes and his ashes thrown to the winds”.
Was Damiens’ pain the most imaginable? How could I have rated my pain as 7 compared to the suffering of Damiens, which is indeed almost unthinkable? How valid was the pain rating in that study after all? How do clinicians and pain patients get along on this level? These were the questions I brought with me to the laboratory as a pain researcher, and these were my concerns with the ‘pain’ terminology over which patients, clinicians and basic scientists often clash.
Here, a distinction should be emphasized between the second-order state of conscious perception of pain, and the first-order state of physiological events (also described as nociception) that correlate with, but do not necessarily lead to, the second-order state. Hence, pain research involving non-human subjects can only infer about pain mechanisms in humans and never assume that a rat ‘in pain’ is indeed ‘in pain’, and if so, how much truly.
Nociception in the cerebellum of the laboratory rat
In an attempt to reproduce the results of the experiment I volunteered in, rats were placed in a fMRI magnet and a noxious chemical (capsaicin) was injected in their hindlimb. From a personal experience, capsaicin really hurts when injected into the skin; ‘how much’ it hurts, though, is a different story (refer to the above argument). This imaging technique indirectly detects the level of brain activity that can be correlated with an external event or a human state of mind. In this study, the aim was to correlate the event of nociception in the rat with the areas in the brain that are more active than the baseline, i.e. seconds before capsaicin injection. The results clearly indicated that regions in the cerebellum of the rat were more active during nociception.
In studies using human subjects, similar findings were reported. In this regard, one can speculate that there is a resemblance between the nociceptive state in the rat and the pain state in the human. However, it was hard to reconcile these findings with classical neuroscience where the cerebellum is described as essentially regulating motor behavior, whereas no significant motion occurred in these studies. Has pain research been neglecting an important ‘pain center’?
The workings of the cerebellum during nociception
Abandoning the rigid sensory-motor discourse, we opted at dealing with the task of understanding the role of the cerebellum in nociception by considering this ‘little brain’ as a system receiving input and output related to nociception, but not necessarily labeled as sensory nor motor. A microelectrode was inserted in the cerebellum of anesthetized rats to record neuronal activity before, and in response to, capsaicin injection. The input was therefore initiated at the site of the injection and transmitted along a pathway to the neurons in the cerebellum. Then, we asked why would neurons in the cerebellum ‘care’ about a peripheral noxious event if they did not have a role in the processing or the modulation of it? If they did, what role would they play in nociception? In fact, when stimulated, the superficial cells of the cerebellum (Purkinje cells) tended to heighten the sensitivity of neurons in the spinal cord pathway that relay visceral nociception (similar to the pathway that relays visceral pain in humans) to noxious colorectal distension. Therefore, the Purkinje cells of the cerebellum seemed to increase nociception, at least that of visceral origin.
From a pain researcher perspective, it is good to travel on a different path and draw attention to novel brain areas involved in the processing of nociceptive information (equally good is to explain its modulation). However, it is not as good as stumbling on anti-nociceptive effects! Considering the microcircuitry of the cerebellum, Purkinje cells in fact inhibit the underlying neurons of the deep cerebellar nuclei, from which originates the final output message of the cerebellum. Therefore, it was reasonable to think that neurons of the deep cerebellar nuclei produce anti-nociceptive effects. Indeed, stimulation of the medial group of deep cerebellar nuclei inhibited the flexion reflex elicited by noxious colorectal distension in the rat. Can this effect be compared to analgesia? In the absence of clinical data, this assumption remains but a challenging speculation.
A hypothetical model for the little brain and pain
Assuming the cerebellum is indispensable for the establishment and regulation of automated motor behavior, why would the cerebellum not also be involved in the regulation of a sensory behavior? Or rather, based on the above information, ‘how’ would the cerebellum conceivably affect our sensation?
What follows is an abstract intellectual exercise based on hunch and loose logical deduction:
“In a situation where Jack twists his ankle, he initially feels pain aggravated by any attempt to move it around. As Jack goes about his daily routine, he is forced to concentrate on his gait while limping to minimize further damage and allow rapid healing. By concentrating, he is allegedly engaging his frontal lobe more than usual, whereas before his accident when his walk was almost automated, he probably used to depend less on his frontal lobe and more on his cerebellum. After using crutches a few days, Jack will walk faster and with more confidence; he probably had enough time to train his cerebellum to take over again and to learn how to walk differently, as he once learned how to ski or ride a bike. When Jack lets go of his crutches next month, thanks to physiotherapy, he will be treading along ‘unconscious’ of the workings of his cerebellum that marvelously corrected those error signals generated by the pain in his ankle. In addition to optimizing his use of the injured limb, the cerebellum might have regulated his brain stem analgesic centers (to which it is extensively connected) to lessen the pain by releasing endogenous opioids”.
Evidently, whether motor or sensory, the influence of the cerebellum on many nociceptive phenomena cannot be treated with skepticism, but should rather be considered as yet another magnifying glass through which new dimensions of pain may be revealed, and as an alarm against scientific dogmatism and distortion. It is customary for neoliberal ideas to rouse polemics and oppositions from the paleoclassical camp, but regardless of which side of the fence pain researchers may stand, the mounting evidence for the involvement of the cerebellum in nociception is pushing for two alternatives: Either reassessment of the intellectual schism practiced between sensory and motor systems, or revision of the definition of pain to accommodate the new findings. Since the first option requires the assembly of a forum beyond the scope of pain specialists alone, the second mission seems more plausible and less pretentious.