Neuropathic Pain in Animal Models of Nervous System Autoimmune Diseases

Table 1

Summary of pain symptoms observed in EAE models and potential therapeutic options for treating MS pain.

EAE	Antigen	Animal model	Test site	Test	Symptoms during disease	Drug	Effects of drug	References
			Tail	Water bath immersion	Heat allodynia (before clinical signs and after resolution)^1
					Cold hyperalgesia^2 (before clinical signs)
Acute	500 𝜇g MBP	♀ 5 wk Lewis rats	Hindpaw	Cold plate analgesia meter	Cold allodynia^3			[23]
					Cold hyperalgesia^3 (during clinical signs)
				Pinch test	Mechanical hyperalgesia (after emergence of clinical signs)
				Electronic von Frey	No significant difference
			Tail	Water bath immersion	Heat allodynia (before clinical signs and after resolution)^1	Gabapentin	Reduce mechanical hyperalgesia	[23]
					Cold hyperalgesia (before clinical signs)^2
			Hindpaw	Cold plate analgesia meter	Cold allodynia^3	Tramadol	Reduce thermal and mechanical hyperalgesia; reduce cold allodynia; known analgesics
CREAE	500 𝜇g MBP+ Cyclosporine A	5 wk ♀ Lewis rats
					Cold hyperalgesia^3 (during recovery)
				Pinch test	Mechanical hyperalgesia (at disease peak and recovery)
				Electronic von Frey	Mechanical allodynia (after clinical signs)	Duloxetine	Reduce thermal hyperalgesia; reduce cold allodynia
CEAE	100 𝜇g GPSCH	♀ Lewis rats	Paws	Hot plate	23% prolonged reaction to noxious heat (hypoalgesia @ wk 10)^4; 58% prolonged reaction to noxious heat (hypoalgesia @ wk 23)^4	ACTH4-9^5	Reduce neurological signs and facilitate recovery of sensory function	[31]
				Hargreaves test	Heat hypoalgesia at disease peak and recovery
CREAE	50 𝜇g MOG35–55	♀ Lewis rats	Hindpaw	Acetone application	Cold allodynia before clinical signs and at disease onset			[22]
				Manual von Frey	Tactile allodynia at disease onset
CREAE	50 𝜇g GPMBP	Lewis rats	Tail	Vocalisation to noxious mechanical stimuli	Ascending pattern of absent vocalisation			[32]
CREAE	150 𝜇g PLP139–151	M/F SJL mice	Tail	Hargreaves test	Heat hypoalgesia at disease peak followed by heat hyperalgesia at disease recovery			[21]
CREAE	40×10^6 T cell blasts^6	♀ SJL mice	Tail	Hargreaves test	Heat hypoalgesia at disease peak followed by heat hyperalgesia at disease recovery			[21]
CREAE	100 𝜇g MOG35–55	♀ C56BL/6J mice	Hindpaw	Electronic von Frey	Mechanical allodynia before clinical signs			[33]
CREAE	50 𝜇g MOG35–55	♀ C56BL/6J mice	Hindpaw	Formalin injection	Hyponociception before clinical signs			[34]
RREAE	35 𝜇g MOG1–125	♂ Dark Agouti rats	Hindpaw	Manual von Frey	Mechanical allodynia (before clinical signs and during recovery)	IL-10 gene therapy^7 (plasmid DNA)	Simulates anti-inflammatory response; Significant decrease of disease severity; Prevention of mechanical allodynia	[35]
CEAE	300 𝜇g MOG35–55	♀ C56BL/6J mice	Paw	Manual von Frey	Mechanical allodynia (during disease course)	Rapamycin^8	Blocks cytokine-driven T-cell proliferation; Reduced EAE development; Inhibition of mechanical allodynia after development of clinical signs	[36]
RREAE	8.75 𝜇g MOG35–55	♂ Dark Agouti rats	Paw	Manual von Frey	Mechanical allodynia (at disease onset)	Ceftriaxone^9	Upregulates glutamate transporter to reduce excess intracellular glutamate and excitotoxicity; Significant decrease of disease severity; Reverse tactile allodynia	[37]

CEAE: chronic experimental autoimmune encephalomyelitis; CREAE: chronic relapsing experimental autoimmune encephalomyelitis; RREAE: relapsing remitting experimental autoimmune encephalomyelitis; MBP: myelin basic peptide; MOG: myelin oligodendrocyte glycoprotein; PLP: proteolipid peptide; GPSCH: guinea pig spinal cell homogenate.
¹42°C; ²2°C; ³cooled from 22°C to 0°C, demonstrating hyperalgesic or allodynic nociceptive behaviour; ⁴54°C; ⁵repeated s.c. injections of ACTH4-9 peptide; ⁶passive immunisation with transfer of PLP_139–151 specific splenocytes from EAE-induced animals; ⁷intrathecal plasmid DNA IL-10F129S, 100 𝜇L at disease onset and 25 𝜇L 3 days later; ⁸1 mg/kg i.p. Rapamycin on D11, and every 2 days thereafter; ⁹daily intrathecal 150 𝜇g ceftriaxone injection at symptom onset.