Table 1: Summary of cited studies on the role of complement in experimental and disease-related pain.

Pain Model	Organism	Experimental Endpoints Measured/span>	Anti Complement Agent	Result	References
Opioid Pain Relief	Mice	Anti-analgesic effect	C3a	C3a reduces the analgesic effect on mice treated with opioid pain medication	[27, 28]
Sciatic Nerve Ligation	Rat	Mechanical Allodynia Cold Allodynia	C5aR antagonist AcF-[OPdChaWR]	Less mechanical and cold allodynia in mice treated with C5aR antagonist	[38]
	C6 (-/-) rats	Mechanical Allodynia Cold Allodynia	NA	Normal neuropathic pain phenotype, MAC not involved
Sciatic Nerve Ligation	Rat	Mechanical hyperalgesia	CVF	Complement depletion reduces pain behavior	[26]
Sciatic Nerve Ligation	Rat	Thermal Hyperalgesia Mechanical Allodynia	Soluble Complement receptor (sCR1)	C3 deposition seen after SCL and IgG injection, accompanied by macrophage recruitment. sCR1 Injections resulted in less TH and MA.	[25]
Spinal inflammatory Neuropathy Caused by Zymosan, GP120, and chronic constriction injury	Rat	Mechanical Allodynia	sCR1	sCR1 injection reduces mechanical allodynia.	[23]
Sciatic Nerve Crush	Rat	Macrophage infiltration and activation	Conmplement inhibitor: Cobra Venom Factor (CVF)	Less macrophage infiltration in CVF-treated animals.	[20]
Sciatic Nerve Chronic constriction injury	Mouse	Hyperalgesia	CVF	Mice given daily injections of CVF had less hyperalgesia. 1 CVF injection 4 days after surgery greatly reduced hyperalgesia.	[30]
Paw Incision	Mouse	Incisional Allodynia and Edema	AcF-[OPdChaWR]	Daily injection of AcF-[OPdChaWR] reduces incisional edema and allodynia.	[35]
Paw injection	Mouse	Heat and Mechanical Hyperalgesia	NA	C5a injection elicits both heat and mechanical hyperalgesia, while C3a injection elicits only mechanical hyperalgesia	[45]
Paw injection	Mouse	Heat Hyperalgesia and Mechanical Allodynia	PMX53 (C5aR antagonist)	Injection of PMX53 reduces both heat hyperalgesia and mechanical allodynia caused by injection of C5a	[46]
Paw Injection	Rat	Edema	Vinblastine	C5a -induced hypernociception reduced when neutraphils reduced by vinblastin treatment.	[43]
		Hypernociception caused by injection of zymosan, carrageenan, LPS, and antigen.	PMX53	PMX53 injection reduced hypernociception.
Rheumatoid Arthritis	Human	C5a	NA	C5a levels increased in rheumatoid joint fluids. Neutraphils increased in synovial fluid.	[53]
Sickle Cell Anemia	Human	Pain, C3a, C3, Bb, C4d,	NA	Measured complement levels in patients suffering severe painful episodes vs. base levels. Complement activation was higher during painful episodes.	[24]
C5a Injection into hindpaw	Rat	Nociception	Hydroxyurea	C5a is a chemotactic peptide, and injection into hindpaw of rats induces hyperalgesia. In addition, PML supernatant also causes hyperalgesia. When PMLs reduced by hydroxyurea treatment, hyperalgesia reduced.	[33]
anti-ganglioside GD2 antibody-induced pain	Rat	Hindpaw allodynia	Non complement-fixing antibody GD2 antibody	Mice treated with mutant antibody with reduced CDC activity had faster resolving allodynia than those injected with "normal" antibody. C6 knockout mice had reduced allodynia, while C5aR antagonist eliminated allodynia.	[47]
C5a receptor knockout	Mouse	Pain, edema	C5aR knockout vs. normal.	In C5aR-/- mice, thermal nociceptive pain reduced for 4 days post-incision, while mechanical sensitivity reduced only after 48 hrs. C5aR-/- showed little edema, while wt mice showed normal edema.	[37]
Hematuria/Groin Pain	Human	C3b	NA	Patients with loin pain and Haematuria had C3b deposition on arteriolar walls.	[16]
Spinal Cord Injury	Rat	Macrophages	Vaccinia Virus Complement Control Protein (VCP)	VCP injection following spinal cord injury inhibits macrophage infiltration and improves hind limb function.	[17]
CFA and C5a injection	Mice	Threshold of pain	PMX53, knockout mice	Showed that pain is mediated by activation of TRPV1 ion channels. NGF is one activator of TRPV1.	[49]
Inflammatory and neuropathic pain	Mice	Hyperalgesia	DF2593A	Showed injection of mice with DF2593A reduces inflammatory and neuropathic pain	[52]