Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry.

Every so often a paper in the pain field appears that shapes new thinking on how we should approach the pain field in terms of translational applications.  The paper by Navratilova and colleagues from the Porreca laboratory indeed has done this with their recent contribution in PNAS:  Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry. 

The notion of emotional processing in pain has in recent years taken on a more salient meaning.  From the writings of Ronald Melzack and Kenneth Casey (Melzack and Casey, 1968), to contributions from Howard Fields (a co-author on this paper) on the unpleasantness of pain (Fields, 1999), the beginnings of a new way of thinking about pain patients is taking place. Since those publications, mainly through functional brain imaging (Becerra et al., 2001), our understanding of reward circuits (including the nucleus accumbens, NAc) in pain have taken on a new and exciting meaning.  Pain relief has recently begun to be considered as a reward (Lenkes et al., 2011) and is clearly a major motivational driver for individuals or organisms to seek to attain a new state of allostasis. Here, the reward of pain relief was demonstrated following peripheral nerve block in rats with incisional injury.

What is so exciting about this report can be defined in three categories:

1. First, is the notion of what the authors define as ‘unmasking’ ongoing or spontaneous pain by using conditioned place preference (CPP), as a metric for pain relief.  The pain field – both preclinical and clinical – now has a much greater focus on measures of so-called spontaneous, rather than evoked, pain.  Of course, this is what bothers patients for most of the time, certainly while awake, rather than evoked pains that can often be avoided. Indeed, this group has used CPP as a measure of pain relief, and now of reward, in animal models of acute and chronic pain (King et al., 2009).
    
2. Second, the very same regions implicated in reward circuits including the one focused on here – dopaminergic drive from the ventral tegmentum (VTA) to the nucleus accumbens, classically associated with positive reinforcement such as addiction – are associated with negative reinforcement produced by pain relief. In incisional injury, relief of pain with a local anesthetic increased dopaminergic signaling from the VTA to the NAc. As their results attest, blockade with lidocaine of afferent input from the periphery produces CPP (as evaluated by behavioral selection of a chamber associated with peripheral nerve block in injured but not sham operated animals) while blockade of VTA to NAc signaling prevents CPP from pain-relief. The authors provide behavioral (CPP), chemical (dopamine microdialysis) and immuohistochemical (c-fos as a measure of neuronal activation in the VTA) evidence for their findings.  Thus, for example, increased c-fos was present in VTA cells positive for tyrosine hydroxylase, a marker of dopamine production. The critical observation was that blockade of dopaminergic receptors in the NAc blocked pain relief-induced CPP.
    
3. Third, the notion that dopaminergic systems may be key to understanding ongoing or chronic pain as well as for improving the discovery of pain treatments is provided by these initial insights in an acute post-surgical pain model. In preclinical studies, activation of dopaminergic systems as a consequence of blockade of afferents in injured animals may provide a way to validate efficacy of novel treatments for ongoing pain with high likelihood of translation to humans.

These exciting initial observations lead, of course, to many new questions.  It is not clear, for example, how these findings relate to chronic pain, and in particular how they are manifest and potentially altered to provide ‘analgesia’.  It is still unclear when chronic pain begins, and the field has not really defined a biology-based process as opposed to the current timeline of persistent pain used by the IASP.  The paper demonstrates that pain relief produces activation of reward pathways but whether this is a general mechanism of pain relief remains to be determined. Clinically, dopaminergic modifying drugs including the antipsychotics/neuroleptics have reported been useful in treatment of some cases of chronic pain and migraine (Seidel et al., 2010; Kelley and Tepper, 2012).  However, such drugs are not used frequently because of their side effect profile even though newer agents have diminished motor effects. Recent neuroimaging studies on chronic pain have shown the increasing importance of the basal ganglia, and in particular the nucleus accumbens, in chronic pain both as a potential marker of pain (Borsook et al., 2011) and as a predictor of chronicity (Baliki et al., 2012).  Finally, chronic pain may be considered to be a ‘reward deficit state’ (see Elman and Borsook, 2011) that has consequences on motivation, cognition and affective processes.  As such, drugs or other treatments that are effective in treatment of ongoing pain will likely alter reward pathways and may also ameliorate states of pain-related co-morbidities including depression and anxiety (e.g., post traumatic stress disorder/PTSD) (see Borsook et al., 2008; Jarcho et al., 2012). The article represents a highly novel approach to preclinical investigations of emotional aspects of ongoing or chronic pain and opens a path for validation of new mechanisms for treatment.

References:

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Becerra L, Breiter HC, Wise R, Gonzalez RG, Borsook D. Reward circuitry activation by noxious thermal stimuli.  Neuron. 2001 Dec 6;32(5):927-46.

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Jarcho JM, Mayer EA, Jiang ZK, Feier NA, London ED.  Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction.  Pain. 2012 Apr;153(4):744-54

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King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, Fields HL, Porreca F. Unmasking the tonic-aversive state in neuropathic pain. Nat Neurosci. 2009 Nov;12(11):1364-6. 

Leknes, S., Lee, M., Berna, C., Andersson, J. & Tracey, I. Relief as a reward: hedonic and neural responses to safety from pain. PLoS One 6, e17870, doi:10.1371/journal.pone.0017870 (2011).

Melzack RC and Casey KL. In The Skin Senses Vol. III  (ed D. R. Kenshalo, Sr.) Ch. 20, 423-443 (Thomas, 1968). J Pain Symptom Manage. 2010 Apr;39(4):768-78. 

Seidel S, Aigner M, Ossege M, Pernicka E, Wildner B, Sycha T. Antipsychotics for acute and chronic pain in adults. J Pain Symptom Manage. 2010 Apr;39(4):768-78.