Pain, Motivation, Migraine, and the Microbiome: New Frontiers for Opioid Systems and Disease

Abstract

For decades the broad role of opioids in addiction, neuropsychiatric disorders, and pain states has been somewhat well established. However, in recent years, with the rise of technological advances, not only is the existing dogma being challenged, but we are identifying new disease areas in which opioids play a critical role. This review highlights four new areas of exploration in the opioid field. The most recent addition to the opioid family, the nociceptin receptor system, shows promise as the missing link in understanding the neurocircuitry of motivation. It is well known that activation of the kappa opioid receptor system modulates negative affect and dysphoria, but recent studies now implicate the kappa opioid system in the modulation of negative affect associated with pain. Opioids are critical in pain management; however, the often-forgotten delta opioid receptor system has been identified as a novel therapeutic target for headache disorders and migraine. Lastly, changes to the gut microbiome have been shown to directly contribute to many of the symptoms of chronic opioid use and opioid related behaviors. This review summarizes the findings from each of these areas with an emphasis on identifying new therapeutic targets. SIGNIFICANCE STATEMENT: The focus of this minireview is to highlight new disease areas or new aspects of disease in which opioids have been implicated; this includes pain, motivation, migraine, and the microbiome. In some cases, this has resulted in the pursuit of a novel therapeutic target and resultant clinical trial. We believe this is very timely and will be a refreshing take on reading about opioids and disease.

Fig. 1.

N/OFQ-NOP receptor fields of research. Promising new research areas discussed within this review are highlighted.

Fig. 2.

Mouse models of chronic migraine–associated pain and opioid-induced hyperalgesia. (A) Mechanical thresholds are determined by von Frey hair stimulation of the periorbital region. (B) To model chronic migraine–associated pain, mice are injected every other day with vehicle or nitroglycerin (10 mg/kg i.p.) and tested on days 1, 5, and 9. To test the effect of PAC1 inhibition, mice were treated with M65 (0.1 mg/kg i.p.) or vehicle on day 10. (C) For OIH, mice were injected twice daily with morphine or vehicle. On days 1–3 they received 20 mg/kg, and on day 4 they received 40 mg/kg s.c. morphine/injection; they are tested on days 1 and 3 of treatment. The effect of M65 was determined on day 5, when cephalic OIH had been established.

Fig. 3.

DOR agonists have been shown to be effective in models of acute and chronic migraine–associate pain (nitroglycerin), negative affect (conditioned place aversion), and aura (cortical spreading depression), as well as in models of posttraumatic headache and medication overuse headache (MOH) related to sumatriptan or morphine (OIH).

Fig. 4.

Summary of topics reviewed. All four opioid receptors modulate analgesia, yet they each have unique established roles, which has led to research into more specialized functions. Mu opioid receptor system has long been known to alter gut motility (prevents diarrhea vs. constipation), but more recently its role in gut microbiome composition has had implications in chronic opioid use disorder; the established primary role for the kappa opioid system is regulation of negative affect with a more recently discovered role in pain-induced negative affect; the delta opioid receptor system has been identified as a promising target for treating headache disorders and migraine, a significant advancement from its more generalized role in chronic pain. Finally, most research thus far has focused on the role of the nociceptin system in depression; here we review recent advances studying its role in motivation as a mechanism to refine treatment approaches.