High Times for Painful Blues : The Endocannabinoid System in Pain-Depression Comorbidity, Marie Fitzgibbon et al., 2016

High Times for Painful Blues : The Endocannabinoid System in Pain-Depression Comorbidity

Marie Fitzgibbon, David P. Finn,  Michelle Roche

International Journal of Neuropsychopharmacology, 2016, 19, (3), 1–20

doi : 10.1093/ijnp/pyv095



Depression and pain are two of the most debilitating disorders worldwide and have an estimate co-occurrence of up to 80%. Comorbidity of these disorders is more difficult to treat, associated with significant disability and impaired healthrelated quality of life than either condition alone, resulting in enormous social and economic cost. Several neural substrates have been identified as potential mediators in the association between depression and pain, including neuroanatomical reorganization, monoamine and neurotrophin depletion, dysregulation of the hypothalamo-pituitary-adrenal axis, and neuro-inflammation. However, the past decade has seen mounting evidence supporting a role for the endogenous cannabinoid (endocannabinoid) system in affective and nociceptive processing, and thus, alterations in this system may play a key role in reciprocal interactions between depression and pain. This review will provide an overview of the preclinical evidence supporting an interaction between depression and pain and the evidence supporting a role for the endocannabinoid system in this interaction.

Keywords : depression, pain, anandamide, cannabinoid, stress


Clinical Data Supporting Depression-Pain Comorbidity Depression and pain are two of the most prevalent psychiatric and neurological disorders worldwide, and both are associated with significant disability, impaired health-related quality of life, and high mortality (Spitzer et al., 1995; Kvien, 2004; Scholich et al., 2012; Hassett et al., 2014). While each is considered a debilitating disorder in its own right, these disease entities frequently coexist, and it has been reported that this association may be as high as 80% of patients (Poole et al., 2009). For example, major depressive and bipolar disorder is associated with painful symptoms in up to 95% of patients (Grover et al., 2012; Maneeton et al., 2013; Nicholl et al., 2014). Similarly, patients suffering from inflammatory and neuropathic pain are up to 4.9 times more likely to develop depression or anxiety disorder than the general population (Hawker et al., 2011; Knaster et al., 2012; Emery et al., 2014; Lin et al., 2015). Patients exhibiting comorbid depression and pain do not respond as effectively to pharmacological treatment, and this comorbidity is more disabling and expensive to both patients and society than either condition alone (Emptage et al., 2005; Gameroff and Olfson, 2006). Furthermore, it has also been found that the severity of depression directly correlates with increased severity of pain symptomatology (Khongsaengdao et al., 2000). However, it should be noted that an intricate relationship exists between depression and pain such that although pain is commonly reported by depressed patients, examination of pain thresholds to various stimuli such as cold, heat, and pressure have been shown to be reduced, increased, or unchanged (Ben-Tovim and Schwartz, 1981; Lautenbacher et al., 1999; Gormsen et al., 2004; Bar et al., 2005; Boettger et al., 2013), effects which depend on the modality and intensity of the stimulus. Thus, given the complex interaction between affect and pain, and the high comorbidity of depression-pain, greater understanding of the neurobiological mechanisms underlying the association is warranted to develop more efficacious treatment strategies. There have been several studies investigating the role of neural substrates, including neuroanatomical organization, neurotransmission, neurotrophins, dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, and inflammation, to name but a few, in the interaction between affect and nociceptive processing (for review, see Blackburn-Munro, 2004; Goesling et al., 2013; Walker et al., 2014). A full review of the role of each of these substrates is beyond the scope of this review.

However, increased evidence has indicated a role for a further substrate, the endogenous cannabinoid (endocannabinoid) system, in affective and nociceptive responding (for reviews, see Finn, 2010; Ashton and Moore, 2011; Gorzalka and Hill, 2011; Rani Sagar et al., 2012; Hillard and Liu, 2014; Jennings et al., 2014; Boychuk et al., 2015) and as such, alterations in this system may provide a common mechanism by which depression and pain coexist. Preclinical animal models provide a valuable means of investigating potential neurobiological substrates that may underlie the association between depression and pain. As such, this review will provide an overview of the preclinical evidence supporting an interaction between depression and pain, the evidence supporting a role for the endocannabinoid system in this interaction, and the potential mechanisms through which the endocannabinoid system may mediate effects on affect and nociceptive processing.


Preclinical Animal Models Support Depression-Pain Interactions

Animal Models of Depression Exhibit Altered Nociceptive Responding

Several animal models of depression based on genetics, stress, lesion, and pharmacological manipulation have been shown to exhibit alterations in nociceptive responding (for review, see Li, 2015), supporting the clinical finding of an association between depression and pain. For example, in rats, the chronic mild stress model of depression has been shown to display a reduced nociceptive threshold to cold (Bardin et al., 2009; Bravo et al., 2012; Bravo et al., 2014) and mechanical (Bardin et al., 2009; Imbe et al., 2012) stimuli and an increased threshold to noxious thermal stimuli (Shi et al., 2010). Furthermore, both inflammatory (Gameiro et al., 2005; Rivat et al., 2010; Wang et al., 2013) and neuropathic (Bravo et al., 2012) pain behavior are enhanced in chronic stress models of depression. Similarly, we and others have shown that the Wistar-Kyoto (WKY) rat, a stress hyperresponsive rat strain with a depressive-like phenotype, exhibits thermal hyperalgesia (Burke et al., 2010), visceral hyperalgesia to colorectal distension (Gibney et al., 2010; Gosselin et al., 2010; O’Malley et al., 2010), enhanced formalin-evoked inflammatory pain behavior (Burke et al., 2010; Rea et al., 2014), and enhanced mechanical allodynia following peripheral nerve injury (neuropathic pain) (Zeng et al., 2008; del Rey et al., 2011). Reserpine-induced monoamine depletion has long been known to result in depressive-like behavior, and recent evidence has demonstrated accompanying thermal allodynia (Liu et al., 2014), as well as pronounced and long-lasting mechanical hyperalgesia and allodynia, and cold allodynia (Nagakura et al., 2009; Arora et al., 2011). Thus, this model has been proposed as a possible rodent model of fibromyalgia (Nagakura et al., 2009). Furthermore, recent work from our group has demonstrated that the olfactory bulbectomised rat, a lesion model of depression, exhibits increased sensitivity to mechanical and thermal stimuli in the von Frey, acetone drop, hot plate, and tail flick tests (Burke et al., 2010, 2013), increased inflammatory pain responding in the formalin test (Burke et al., 2010), and enhanced neuropathic pain responding following spinal nerve ligation (Burke et al., 2013, 2014). Thus, taken together, several animal models of depression have been shown to exhibit altered nociceptive thresholds and enhanced inflammatory and neuropathic pain behavior, mimicking effects observed clinically.