Distinguishing analgesic drugs from non-analgesic drugs based on brain activation in macaques with oxaliplatin-induced neuropathic pain.

The antineoplastic agent oxaliplatin is a first-line treatment for colorectal cancer. However, neuropathic pain, characterized by hypersensitivity to cold, emerges soon after treatment. In severe instances, dose reduction or curtailing treatment may be necessary. While a number of potential treatments for oxaliplatin-induced neuropathic pain have been proposed based on preclinical findings, few have demonstrated efficacy in randomized, placebo-controlled clinical studies. This failure could be related, in part, to the use of rodents as the primary preclinical species, as there are a number of distinctions in pain-related mechanisms between rodents and humans. Also, an indicator of preclinical pharmacological efficacy less subjective than behavioral endpoints that is translatable to clinical usage is lacking. Three days after oxaliplatin treatment in Macaca fascicularis, a significantly reduced response latency to cold (10 °C) water was observed, indicating cold hypersensitivity. Cold-evoked bilateral activation of the secondary somatosensory (SII) and insular (Ins) cortex was observed with functional magnetic resonance imaging. Duloxetine alleviated cold hypersensitivity and significantly attenuated activation in both SII and Ins. By contrast, neither clinically used analgesics pregabalin nor tramadol affected cold hypersensitivity and cold-evoked activation of SII and Ins. The current findings suggest that suppressing SII and Ins activation leads to antinociception, and, therefore, could be used as a non-behavioral indicator of analgesic efficacy in patients with oxaliplatin-induced neuropathic pain.

Pain-related behavior and brain activation in cynomolgus macaques with naturally occurring endometriosis.

STUDY QUESTION: Can pain be objectively assessed in macaques with naturally occurring endometriosis? SUMMARY ANSWER: Behavioral, pharmacological and in vivo brain imaging findings indicate that pain can be quantified in macaques with endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is characterized by abdominopelvic hypersensitity. The mechanism by which endometriosis evokes pain is largely unknown, as currently available analgesics offer limited pain relief. Thus, there is a need for both greater understanding of the in vivo mechanism of endometriosis-associated pain and better methods of testing novel therapeutics. STUDY DESIGN, SIZE, DURATION: Pain-related behavior and brain activation were assessed in five cynomolgus macaques with endometriosis. Three healthy female macaques served as controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Abdominopelvic sensitivity to force was assessed with an algometer. Activation of brain areas using block design force stimulation and the effects of a single dose of the analgesic drug morphine and 2-month treatment with the progestin dienogest on brain activation were observed via functional magnetic resonance imaging. MAIN RESULTS AND THE ROLE OF CHANCE: Pain response thresholds in macaques with endometriosis were significantly less than that of healthy macaques (P = 0.0003). In addition, non-noxious force activated the insula and thalamus, which was reduced with morphine and 2-month dienogest treatment. LIMITATIONS, REASONS FOR CAUTION: The specific role of cysts, such as peritoneal cysts, in endometriosis pain was not explored. While non-noxious stimulation activated the insula and thalamus, macaques were sedated during fMRI scans. Current findings need further confirmation in a larger cohort. WIDER IMPLICATIONS OF THE FINDINGS: The current study demonstrated central sensitization and related pain behavior in macaques with naturally occurring endometriosis. Altered functioning of the central nervous system could be the focus of future mechanistic studies and for the development of novel therapeutics. STUDY FUNDING/COMPETING INTEREST(S): Supported by a grant from the Shizuoka Industrial Foundation. All authors are employees of Hamamatsu Pharma Research, Inc.

Gaps in Understanding Mechanism and Lack of Treatments: Potential Use of a Nonhuman Primate Model of Oxaliplatin-Induced Neuropathic Pain.

The antineoplastic agent oxaliplatin induces an acute hypersensitivity evoked by cold that has been suggested to be due to sensitized central and peripheral neurons. Rodent-based preclinical studies have suggested numerous treatments for the alleviation of oxaliplatin-induced neuropathic pain, but few have demonstrated robust clinical efficacy. One issue is that current understanding of the pathophysiology of oxaliplatin-induced neuropathic pain is primarily based on rodent models, which might not entirely recapitulate the clinical pathophysiology. In addition, there is currently no objective physiological marker for pain that could be utilized to objectively indicate treatment efficacy. Nonhuman primates are phylogenetically and neuroanatomically similar to humans; thus, disease mechanism in nonhuman primates could reflect that of clinical oxaliplatin-induced neuropathy. Cold-activated pain-related brain areas in oxaliplatin-treated macaques were attenuated with duloxetine, the only drug that has demonstrated clinical efficacy for chemotherapy-induced neuropathic pain. By contrast, drugs that have not demonstrated clinical efficacy in oxaliplatin-induced neuropathic pain did not reduce brain activation. Thus, a nonhuman primate model could greatly enhance understanding of clinical pathophysiology beyond what has been obtained with rodent models and, furthermore, brain activation could serve as an objective marker of pain and therapeutic efficacy.

Pain-Related Behavior and Brain Activation in a Cynomolgus Macaque Model of Postoperative Pain.

BACKGROUND: Inadequate postoperative pain management could lead to persistent pain and this is, in part, due to incomplete understanding of the mechanism of postoperative pain. Currently available rodent models may have limited translatability to clinical postoperative pain. Thus, a preclinical model of postoperative pain was developed in the cynomolgus macaque, a species that is phylogenetically closer to humans than rodents. METHOD: The presence of pressure hypersensitivity was assessed with non-noxious pressure applied proximally and distally (approximately 10 cm) to an abdominal incision in macaques. The effect of the opioid morphine (intramuscular, i.m.), the nonsteroidal anti-inflammatory drug diclofenac (i.m.) and the anticonvulsant pregabalin (i.m.) on pressure hypersensitivity was evaluated one and two days following surgery. Brain activation during non-noxious pressure stimulation was observed with functional magnetic resonance imaging. RESULTS: Hypersensitivity to non-noxious pressure applied proximally and distally (approximately 10 cm) to the incision was observed, lasting for up to seven days and three days, respectively, following surgery. Postoperative pressure hypersensitivity was attenuated with morphine but not with either diclofenac or pregabalin. Bilateral activation of the insular cortex and cingulate cortex was observed during non-noxious pressure stimulation proximal to the incision, which was attenuated with morphine. By contrast, pregabalin reduced only cingulate cortex activation. CONCLUSION: The lack of antinociceptive efficacy of pregabalin on postoperative pain could be due to the incomplete suppression of pressure-evoked brain activation. It is speculated that incomplete postoperative pain relief observed in general could be due to residual or persistent activity of key pain nuclei such as the insular cortex. The current macaque model could be used for further elaborating the mechanism of postoperative pain as well as confirming the efficacy of potential treatments for the management of postoperative pain.