Abstract
BackgroundApproximately 20% of the adult population suffer from chronic pain that is not adequately treated by current therapies, highlighting a great need for improved treatment options. To develop effective analgesics, experimental human and animal models of pain are critical. Topically/intra-dermally applied capsaicin induces hyperalgesia and allodynia to thermal and tactile stimuli that mimics chronic pain and is a useful translation from preclinical research to clinical investigation. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored.MethodologyHere we establish an aversive capsaicin-induced fMRI model using non-noxious heat stimuli in Cynomolgus monkeys (n = 8). BOLD fMRI data were collected during thermal challenge (ON:20 s/42°C; OFF:40 s/35°C, 4-cycle) at baseline and 30 min post-capsaicin (0.1 mg, topical, forearm) application. Tail withdrawal behavioral studies were also conducted in the same animals using 42°C or 48°C water bath pre- and post- capsaicin application (0.1 mg, subcutaneous, tail).Principal FindingsGroup comparisons between pre- and post-capsaicin application revealed significant BOLD signal increases in brain regions associated with the ‘pain matrix’, including somatosensory, frontal, and cingulate cortices, as well as the cerebellum (paired t-test, p<0.02, n = 8), while no significant change was found after the vehicle application. The tail withdrawal behavioral study demonstrated a significant main effect of temperature and a trend towards capsaicin induced reduction of latency at both temperatures.ConclusionsThese findings provide insights into the specific brain regions involved with aversive, ‘pain-like’, responses in a nonhuman primate model. Future studies may employ both behavioral and fMRI measures as translational biomarkers to gain deeper understanding of pain processing and evaluate the preclinical efficacy of novel analgesics.
Highlights
Pain, especially chronic pain, that occurs during inflammatory or neuropathic conditions remains poorly treated
Primary hyperalgesia and allodynia to heat, tonic pressure and touch occurs at the site of tissue injury as a result of peripheral sensitization of nociceptive neurons, whereas central sensitization causes secondary hyperalgesia and allodynia to mechanical/tactile stimuli that extends into uninjured tissue surrounding a nerve injury
It has been shown that both primary and secondary hyperalgesia and allodynia can be experimentally induced in healthy volunteers using the heat/capsaicin sensitization model [11], where topical/intradermal administration of capsaicin induces both types of sensitization at the site of application as well as episodic burning pain sensation around the site of application [7, 12,13,14]
Summary
Especially chronic pain, that occurs during inflammatory or neuropathic conditions remains poorly treated. In an attempt to provide better treatments, significant efforts have been devoted to establish experimental models of pain in both animals [3, 4] and humans [5,6,7,8], including nerve ligation, various neuropathy models, acute chemotherapy-induced neuropathy, and neuropathy as a result of HIV medication Often these models of pain are combined with mechanical or thermal stimulation either to examine evoked reflex responses in animals or altered psychophysics in humans, and to characterize allodynia and/or hyperalgesia symptoms that commonly manifest in numerous clinical pain disorders including neuropathic, inflammatory and osteoarthritic pain [4, 9, 10]. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored
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