Table 3.
Cellular mediators of acute, transitional, and chronic incisional pain.
| Location | Target | Model/incision type | Species | Altered expression | Substance | Pain behavior | Ref | |
|---|---|---|---|---|---|---|---|---|
| Acute | Spinal cord | AMPA | Plantar incision | Rats | i.t. or i.p. LY293558 (non-NMDA receptor antagonist) | Reduced mechanical hypersensitivity | (110) | |
| Spinal cord | AMPA/Kainate | Gastrocnemius incision | Rats |
i.t. NBQX (AMPA/KA antagonist) 2 h postop i.t. JSTX (Joro spider toxin) (Ca2+ permeable non-NMDA receptors antagonist) 2 h postop |
Reduced secondary mechanical hyperalgesia 2 h–2 days postop | (111) | ||
| PNS | ASIC3 | Plantar incision | Rats | Increased in ipsilateral DRG 24 h after incision |
i.pl. APETx2 during surgery i.t. siRNA (once a day for 4 days preop) |
Reduced non-evoked pain and heat hyperalgesia 24 h postop | (112) | |
| PNS | C5a (Complement component C5) | Plantar incision | Mice |
Increased C5a in plantar skin from 2 to 72 h Increased C5aR in plantar skin from 24 to 72 h |
i.pl. C5aR antagonist 1 h preop, then 2 h before behavior | Reduced thermal and mechanical hypersensitivity | (113) | |
| PNS | CCL17 and CCL22 | Plantar incision | Mice |
Increased CCL17 in plantar skin from 3 to 6 h Increased CCL22 in plantar skin from 24 to 72 h |
i.pl. C021 (CCR4 antagonist) 1 h preop i.pl. C021 24 h postop CCR4KO (constitutive, global) |
Reduced mechanical hypersensitivity at 1 h (not thermal) postop Reduced mechanical and thermal hypersensitivity 1 h after C021 Reduced mechanical hypersensitivity 14 h–72 h postop |
(114) | |
| Spinal cord | GluR1 (linked to AMPA) | Plantar incision | Rats | Increased DH surface delivery of GluR1 at 3 h on ipsilateral side + interaction with stargazin (regulates synaptic targeting of AMPA) increased |
i.t. Stargazin siRNA twice a day for 3 consecutive days preop |
Reduced mechanical hypersensitivity at 3 h postop | (115) | |
| PNS | IL-1 | Plantar incision | Mice |
IL-1rKO IL-1raTG (IL-1 receptor antagonist overexpression) s.c. IL-1ra chronic micropump from 3 days preop OR i.p. 30 min before sensory testing on POD 1 |
Reduced mechanical hypersensitivity | (116) | ||
| PNS | IL-10 | Plantar incision | Rats |
Increased in plantar skin at 4, and 48 h Increased in muscle from 1 h–10 days |
(117) | |||
| PNS | IL-1ß | Plantar incision | Mice | Increased in plantar skin from 2 to 72 h | i.pl. Anakinra (antagonist) 2 h preop, then daily 2 h before behavior | Reduced mechanical and thermal hyperalgesia | (118) | |
| PNS | IL-1ß | Plantar incision | Rats |
Increased in plantar skin from 1 to 48 h Increased in muscle from 1 to 4 h |
(117) | |||
| PNS | IL-6 | Plantar incision | Rats |
Increased in plantar skin from 1 to 48 h Increased in muscle 1 h–10 days |
(117) | |||
| PNS | Nav1.7 | Plantar incision | Mice | i.pl or s.c. Pn3a (selective Nav1.7 inhibitor) 24 h postop | Reduced mechanical hypersensitivity | (119) | ||
| PNS | Neutrophils | Plantar incision | Mice | Increased in plantar skin from 2 to 72 h |
i.v. Vinblastine sulphate 72 h preop i.v. Anti-neutrophil antibody 7 days and 24 h preop |
Reduced mechanical hypersensitivity | (120) | |
| PNS | NGF | Plantar incision | Rats | Increased in plantar skin from 4 h–10 days | i.p. Anti-NGF antibody 1 day preop |
Reduced non-evoked pain 4–48 h postop Reduced heat hyperalgesia 24–48 h No change to mechanical threshold |
(121) | |
| PNS/CNS | NMDA receptors | Plantar incision | Rats | s.c. Ketamine perioperatively | No change | (122) | ||
| PNS/CNS | Opioid receptors | Plantar incision | Rats | s.c. Fentanyl perioperatively |
Reduced mechanical hypersensitivity at Increased mechanical hypersensitivity POD1 to POD5, and non-evoked pain D0–POD4 |
(122) | ||
| PNS/CNS | Opioid receptors | Plantar incision | Rats | s.c. Naloxone POD 8 | No change | (122) | ||
| Spinal cord | PKCγ (linked to GluR1 and AMPA) | Plantar incision | Rats | Increased DH membrane translocation on ipsilateral side at 3 h | i.t. PKCγ siRNA twice a day for 3 consecutive days preop | Reduced mechanical hypersensitivity at 3 h postop | (123) | |
| Transition from acute to chronic | CNS | 5-HT3 receptor | Plantar incision + NTX (naltrexone) POD 21 | i.t. Ondansetron (5-HT3 receptor antagonist) at time of s.c. NTX injection | Prevented NTX-induced mechanical and thermal hyperalgesia | (124) | ||
| Spinal cord | MOR/DOR/KOR | Plantar incision | Mice | i.t. CTOP (MOR-selective inhibitor)/naltrinode and TIPP (DOR-selective inhibitors)/nor-BNI and LY24,56,302 (KOR inhibitors) on POD 21 | Reinstated mechanical hyperalgesia with MOR and KOR-selective antagonists | (125) | ||
| CNS | NMDA receptors | Plantar incision + fentanyl + naloxone on POD 8 | Rats | s.c. Ketamine perioperatively |
Prevented fentanyl-enhanced hyperalgesia, and naloxone-induced hyperalgesia on POD 8 Improved efficacy of morphine on POD 1 |
(122) | ||
| CNS | NMDA receptors | Plantar incision + remifentanil + nor-BNI on POD 21 | Mice | s.c. MK-801 (prior to nor-BNI) | Prevented nor-BNI-induced hyperalgesia | (126) | ||
| CNS | Opioid receptors | Plantar incision + fentanyl | Rats | s.c. Naloxone on POD 8 | Reinstated mechanical hyperalgesia and non-evoked pain | (122) | ||
| CNS | Opioid receptors/KOR | Plantar incision + remifentanil | Mice | s.c. Naloxone/naloxone-methiodide (peripherally-restricted)/nor-BNI on POD 21 | Reinstated mechanical hyperalgesia with naloxone and nor-BNI up to 5 months postop | (126) | ||
| Spinal cord | PKMζ | Plantar incision + i.pl. PGE2 at day 15 | Mice | i.t. ZIP (PKMζ inhibitor) on POD 13 | Prevented persistent mechanical hypersensitivity induced by i.pl. PGE2 injection | (127) | ||
| Chronic | Spinal cord | IL-1ß | SMIR | Rats | Increased in ipsilateral DRG from 5 to 20 days | i.t. IL-1ra (IL-1ß inhibitor) 30 min preop and for 10 consecutive days postop | Reduced mechanical hyperalgesia | (128) |
| Spinal cord | P2X7R | SMIR | Rats | Increased in ipsilateral dorsal horn from 1 to 22 days | i.t. BBG or A438079 (P2X7R antagonists) 30 min preop and for 7 consecutive days postop | Reduced mechanical hyperalgesia | (129) | |
| Spinal cord | p38 | SMIR | Rats | Increased in ipsilateral DRG from 5 to 20 days | i.t. SB203580 (p38 inhibitor) 30 min preop and for 10 consecutive days postop | Reduced mechanical hyperalgesia | (128) | |
| Spinal cord | TLR4 | SMIR | Rats | Increased in ipsilateral DRG from 5 to 20 days | i.t. LPS-RS (TLR4 inhibitor) 30 min preop and for 10 consecutive days postop | Reduced mechanical hyperalgesia | (128) |
CNS, central nervous system; DH, dorsal horn; DOR, δ opioid receptor; DRG, dorsal root ganglion; i.p., intraperitoneal; i.pl. intraplantar; i.t., intrathecal; KOR, κ opioid receptor; MOR, µ opioid receptor; PNS, peripheral nervous system; POD, postoperative day; Postop, postoperatively; Preop, preoperatively; s.c., subcutaneous; SMIR, skin and muscle incision retraction.