Pain-Sensing Nerve Fibers Display Reduced Activity in Models of Aging and Truly Chronic Pain
Material below summarizes the article Nociceptor Sensitization Depends on Age and Pain Chronicity, published on January 8, 2016, in eNeuro and authored by Andy D. Weyer, Katherine J. Zappia, Sheldon R. Garrison, Crystal L. O’Hara, Amanda K. Dodge, and Cheryl L. Stucky.
As we gain traction in curing diseases, one of the biggest battles still being fought is the problem of chronic pain.
Worldwide, millions of individuals suffer from chronic pain, which impacts quality of life and prevents many people from maintaining employment. Yet, for the majority of patients, treatment options are woefully insufficient. For instance, opioids, the treatment of choice for acute pain, are contraindicated for chronic usage due to many side effects and their abuse potential, and newer anticonvulsants prescribed for pain are only effective for about one-third of patients.
Thus, it is widely agreed that new analgesics that can reduce pain symptoms and increase quality of life must be identified. However, the lack of pharmacologic options is not for lack of trying. Over the past decade, countless drugs showing promise in preclinical studies have failed to gain approval by regulatory agencies.
While there are a myriad of reasons, two points stand out. First, most pre-clinical basic pain research utilizes young rodents, despite evidence indicating that chronic pain prevalence increases with age in humans. Second, most pre-clinical pain research utilizes animal models in which “chronic” pain of short duration (a few days to a few weeks) is examined, rather than truly chronic pain lasting months to years that is treated clinically.
It is also unclear whether novel analgesics for chronic pain should be designed against targets in the peripheral nervous system (PNS), which senses and transmits painful stimuli, or the central nervous system, which is responsible for the ultimate interpretation of incoming pain signals.
In this study, we set out to address these shortcomings by examining the specific contribution of the PNS to both acute and truly chronic pain states, and to determine whether the mechanisms of pain sensation change with age in a rodent model of inflammatory pain.
To model inflammatory pain, we utilized the Complete Freund’s Adjuvant (CFA) model of inflammation, in which CFA is injected subcutaneously into the mouse’s hind paw. These injections generated persistent inflammation for at least eight weeks after injection, and led to corresponding pain behaviors until at least this time point in animals young (eight weeks old) and aged (older than 1.5 years).
However, we observed that young animals exhibited greater sensitization to mechanical stimuli following CFA injury than their aged counterparts at both acute (two days post-injection) and chronic (eight weeks post-injection) time points. This contradicts clinical literature showing aged individuals repeatedly report greater pain than younger individuals.
To learn whether these differences in age-related pain behavior were mediated at the CNS or PNS levels, we recorded mechanically-evoked action potentials from isolated nociceptive primary afferents innervating the inflamed paw via the ex vivo skin-nerve preparation.
In accord with previously published reports from our lab and others, nociceptive C fiber afferents from young animals doubled in the number of action potentials fired in response to a mechanical stimulus as compared to control animals after two days of acute CFA inflammation. This sensitization allows the periphery to better communicate a sensation of pain to the CNS, causing us to avoid potentially injurious stimuli.
In stark contrast, when we examined the firing of C fibers from aged, inflamed animals, we found that there was only a trend for elevated firing. This reflected our behavioral data, whereby aged animals exhibited lesser pain responses than young animals.
While these findings were unexpected based on the clinical literature, we were more interested in exploring the mechanisms of pain after eight weeks of inflammation, since this time point more closely mirrors chronic pain.
When examining the firing of C fibers in response to mechanical stimuli at this time point, we were shocked to find that C fiber firing rates were lower than controls, despite continued prominent pain exhibited by these animals behaviorally.
In contrast, C fibers from aged animals again showed only a trend for this reduced firing. Importantly, this finding was not specific to mechanical stimuli, as chronically-inflamed afferents also demonstrated reduced responses to the pungent chemical capsaicin as compared to controls.
Collectively, this study proposes two major findings. First, there appears to be a disconnect between clinical literature and basic science literature on the effect of aging on pain. In contrast to the clinical literature, aged animals appear to be less malleable than young animals in the face of a painful inflammatory injury at both the behavioral and primary afferent levels. Future studies must explore whether this is a true species difference, or whether rodent behavioral assays are insufficient for capturing the full complexity of pain sensation.
Second, our data indicate that the basic mechanisms by which we sense pain may be very different during the acute and chronic pain phases, at least for an inflammatory injury. While research by our lab and others has consistently demonstrated that primary afferents are sensitized to mechanical stimuli acutely following inflammation (within a few days), few studies have examined the response properties of primary afferents during a truly chronic injury, such as the eight week time point explored here.
Investigation of this wider timespan revealed that a biological switch occurs as pain evolves over time. The sensitized primary afferents observed during acute pain become desensitized to mechanical stimuli during chronic pain, perhaps in an effort to limit the pain signal that is communicated to the CNS. This phenomenon appears to have been largely missed as a result of the short duration time points in most pre-clinical “chronic” pain studies. As a consequence, these afferent recordings indicate that the prominent pain behaviors observed during chronic pain states are likely due in large part to central mechanisms. Future studies utilizing spinal cord and brain recordings will be required to confirm this.
More broadly, these findings may illuminate why many novel drugs have proven to be ineffective in ameliorating chronic pain in patient populations. Future experimental analgesics must be tested in truly chronic models of pain to evaluate their efficacy as potential therapeutics for chronic pain.
Nociceptor Sensitization Depends on Age and Pain Chronicity. Andy D. Weyer, Katherine J. Zappia, Sheldon R. Garrison, Crystal L. O’Hara, Amanda K. Dodge, Cheryl L. Stucky. eNeuro Jan 2016, 3 (1). DOI: 10.1523/ENEURO.0115-15.2015