Pain without unpleasantness
Scientists may have discovered how to take the hurt out of pain. In mice.
Pain asymbolia is a rare and fascinating condition where pain is experienced without suffering. If someone with pain asymbolia gets injured, they can feel the intensity and location of the noxious stimulus, and they will describe that feeling as “pain.” But they don’t experience the pain as being unpleasant, and they aren’t motivated to avoid it. In technical terms, this means that the “sensory discriminative” dimension of pain is present, but the “affective motivational” dimension is missing. Why does this occur? Pain asymbolia is caused by damage in the limbic system, which controls affect and motivation.
The reason I mention this is that a recent study describes successful efforts to basically give pain asymbolia to mice by inhibiting a population of pain-specific neurons in the amygdala. (Thanks to Paul Ingraham at PainScience.com for pointing it out on Twitter.)
The study is fascinating, and provides a lot of insight into how pain perception works, and how we might someday come to understand it much better. Following are some details and relevant quotes.
The role of the basolateral amygdala in pain
The authors of the study were interested in the basolateral amygdala (BLA), because it is known that damage to this area can result in pain asymbolia:
The amygdala critically contributes to the emotional and autonomic responses associated with valence coding of neural information, such as responses during fear or pain. Damage to the basolateral amygdala (BLA) can induce a rare phenomenon in which noxious stimuli remain detected and discriminated but are devoid of perceived unpleasantness and do not motivate avoidance.
Further, the BLA seems to play a role in chronic pain:
the BLA displays heightened activity during chronic pain, and … neural hyperactivity and altered functional connectivity in the amygdala parallel the onset of chronic pain, suggesting that the BLA might play a critical role in shaping pathological pain perceptions.
The footnotes in support of this claim reference studies by Vania Apkarian and colleagues, which I discuss in this post.
Imaging the activity of the BLA
The authors used (very complicated!) imaging techniques to assess the activity of neurons in the BLA during a variety of stimuli. They found that a certain subset of neurons (referred to as the “neural ensemble”) were active during noxious but not non-noxious stimuli:
This ensemble was composed of multimodal responsive neurons, as well as a unique population that appeared to encode nociception selectively and no other sensory information …
One crucial finding was that greater activation of this BLA nociceptive ensemble was predictive of increased pain behaviors, suggesting that BLA nociceptive processing influences the magnitude of pain behaviors.
This finding was interesting to me because my understanding is that other attempts to find “pain signatures” in the brain have not identified any areas that are specific to pain. Perhaps this is an advance that will increase our understanding of exactly which parts of the brain matter most for chronic pain.
BLA inhibition and pain-related behavior
To test whether the activity of the neural ensemble in the BLA plays a causal role in pain, the authors used (very complicated!) techniques to inhibit its activity. It was found that the BLA-inhibited mice reflexively withdrew from noxious stimuli, but were less motivated to avoid them. The authors concluded that:
this BLA nociceptive ensemble transforms emotionally inert nociceptive information into an affective signal that is necessary for the selection and learning of motivational protective pain behaviors.
BLA inhibition and chronic pain
The authors next looked at the role of the BLA is the development of chronic pain and allodynia, which means pain caused by innocuous stimuli such as light touch or cold temperature.
A hallmark of chronic neuropathic pain is the appearance of allodynia and hyperalgesia, both pathological perceptual states in which aversion is ascribed to innocuous somatosensory stimuli and exacerbated in response to noxious stimuli, respectively. We hypothesized that this pathological perceptual switch might result from maladaptive transformations in BLA coding.
It was found that the neural ensemble became active in response to light touch in mice with a sciatic nerve injury, but remained inactive in uninjured mice.
These results suggest a role for the BLA in the emergence of allodynia in chronic pain states.
The scientists then tried to prevent alloydynia caused by sciatic nerve injury by inhibiting the neural ensemble. This did not reduce reflexive responses to noxious stimuli, but dramatically decreased other pain-related behaviors:
While the injection of CNO in neuropathic TRAPhM4 mice did not alter reflexive hypersensitivity, we observed a profound decrease in neuropathic affective-motivational behaviors, regardless of stimulus intensity or modality.
Further, the BLA-inhibited mice with sciatic nerve injury did not avoid cold, which is not the normal behavior in the presence of neuropathic injury.
CNO administration to neuropathic TRAPhM4 mice generated a near-total indifference between cold and neutral temperature chambers.
The authors concluded that:
disrupting neural activity in a nociceptive ensemble in the BLA is sufficient to reduce the affective dimension of pain experiences, without altering their sensory component.
Here are some final quotes from the paper summarizing the meaning of the findings:
The presence of a purely nociceptive-specific subpopulation of neurons within the larger BLA nociceptive ensemble, distinct from general aversion-encoding populations, suggests the capacity for computing and assigning an accompanying “pain tag” to valence information. …
This critical node in the nociceptive brain circuitry plays a critical role in shaping pain experiences, by providing an evaluation of nociceptive information that, in turn, intrinsically motivates protective behaviors associated with pain.
And the implications of the study for chronic pain in humans:
Clinical management of chronic pain remains a staggering challenge [and] comprehensive strategies that provide substantive relief across pain types are urgently needed …
This finding may enable the development of chronic pain therapies that could selectively diminish pain unpleasantness, regardless of etiology, without influencing reward, and importantly, preserving reflexes and sensory discriminative processes necessary for the detection and localization of noxious stimuli.
I see this result as an encouraging sign that reductionist and brain-centric techniques for understanding and controlling pain may be making progress. It’s a welcome change from the all-too common experience of reading papers where the main takeaway is something like “wow pain is so complex!” or “we know even less than we thought we knew.”