Distinct BOLD fMRI Responses of Capsaicin-Induced Thermal Sensation Reveal Pain-Related Brain Activation in Nonhuman Primates.
BACKGROUND
Approximately 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.


METHODS
Here 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).


RESULTS
Group 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.


CONCLUSIONS
These 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.
Translational Biomarkers, Merck Research Laboratories, MSD, Singapore, Singapore.
Abu Bakar Ali
AB
Asad
Translational Biomarkers, Merck Research Laboratories, MSD, Singapore, Singapore.
Stephanie
S
Seah
Biometrics Research, Biostatistics & Research Decision Sciences, Merck Research Laboratories, Merck & Co., Rahway, NJ, United States of America.
Richard
R
Baumgartner
Biometrics Research, Biostatistics & Research Decision Sciences, Merck Research Laboratories, Merck & Co., Rahway, NJ, United States of America.
Dai
D
Feng
Early Discovery Pharmacology, Merck Research Laboratories, MSD, Singapore, Singapore.
Andres
A
Jensen
Imaging, Maccine Pte Ltd, Singapore, Singapore.
Elaine
E
Manigbas
Early Discovery Pharmacology, Merck Research Laboratories, MSD, Singapore, Singapore.
Brian
B
Henry
Early Discovery Pharmacology, Merck Research Laboratories, Merck & Co., West Point, PA, United States of America.
Andrea
A
Houghton
Translational Biomarkers, Merck Research Laboratories, Merck & Co., West Point, PA, United States of America.
Jeffrey L
JL
Evelhoch
Dept of Psychology, National University of Singapore, Singapore, Singapore.|A*STAR-NUS Clinical Imaging Research Centre, Singapore, Singapore.
Stuart W G
SW
Derbyshire
Translational Biomarkers, Merck Research Laboratories, MSD, Singapore, Singapore.
Chih-Liang
CL
Chin
D000818:Animals; D002211:Capsaicin / Q000009:adverse effects*; D002531:Cerebellum / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D005625:Frontal Lobe / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000503:physiopathology; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000503:physiopathology; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000503:physiopathology; D013003:Somatosensory Cortex / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000503:physiopathology; D013623:Tail; D013697:Thermosensing / Q000502:physiology
D002211:Capsaicin