Journal of Pharmacology and Pharmacotherapeutics

RESEARCH LETTER
Year
: 2013  |  Volume : 4  |  Issue : 3  |  Page : 208--210

Modulation of inflammatory pain in response to a CCR2/CCR5 antagonist in rodent model


Masayuki Okamoto, Takeshi Suzuki, Nobuhide Watanabe 
 Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho Company Limited, Japan

Correspondence Address:
Masayuki Okamoto
Masayuki Okamoto, 363, Shiosaki Hokusei-CHO, Inabe-Shi, MIE, 511-0406
Japan




How to cite this article:
Okamoto M, Suzuki T, Watanabe N. Modulation of inflammatory pain in response to a CCR2/CCR5 antagonist in rodent model.J Pharmacol Pharmacother 2013;4:208-210


How to cite this URL:
Okamoto M, Suzuki T, Watanabe N. Modulation of inflammatory pain in response to a CCR2/CCR5 antagonist in rodent model. J Pharmacol Pharmacother [serial online] 2013 [cited 2020 May 24 ];4:208-210
Available from: http://www.jpharmacol.com/text.asp?2013/4/3/208/114605


Full Text

Sir,

Chemokines are small (8 to 14 kDa) secreted chemotactic cytokines that interact with G-protein-coupled receptors with a highly conserved seven-transmembrane domain. They play essential roles in recruiting leukocytes to sites of injury, infection and inflammation. There are four groups of chemokines, which are divided according to their characteristic cysteine sequence motifs: The CXC, CC, CX3C and C families.

C-C chemokine ligand 2 (CCL2), previously referred to as monocyte chemoattractant protein-1 (MCP-1), a 78 amino acid secreted protein, belongs to the CC subfamily and controls the recruitment of monocytes, memory T-cells and natural killer cells to sites of inflammation through its chemokine receptor. CCL2 binds to Chemokine receptor type 2 (CCR2), the receptor for CCL2, exclusively and with a high affinity. CCL2 has been implicated as an important mediator of several diseases, including multiple sclerosis, rheumatoid arthritis, diabetes, and atherosclerosis. We previously reported that a CCR2 antagonist reduced swelling and joint destruction in rat models of rheumatoid arthritis and nearly produced a complete resolution of symptoms in a mouse model of multiple sclerosis. [1] In addition, recent reports suggest that chemokines may play roles in the experience of pain. [2],[3],[4] Indeed, Abbadie reported that CCR2-deficient mice showed a decrease in paw lifting and licking in a formalin-induced inflammation model. Furthermore, in response to nerve ligation, the persistent and marked up-regulation of CCR2 mRNA was evident in the nerve and dorsal root ganglia. [5] These results suggest that CCL2 may contribute to both inflammatory and neuropathic pain states. In this study, we investigated whether our CCR2 antagonist might exhibit an anti-nociceptive effect in animal models.

TLK48462, a novel dual antagonist of CCR2 and Chemokine receptor type 5 (CCR5) antagonist (CCR2/CCR5 antagonist), inhibited chemotaxis mediated by human CCL2 and human C-C chemokine ligand 4 (CCL4) with a similar potency. The chemotaxis of human PBMC (peripheral blood mononuclear cell) IC 50 values for CCL2 and CCL4 were 1.2 μM and 1.8 μM, respectively. We also confirmed that TLK48462 inhibited chemotaxis mediated by human and rat CCL2 with similar potencies. The chemotaxis of rat spleen cells IC 50 values was 0.4 μM.

We first evaluated the effect of TLK48462 using a formalin test. Animal care and experimental procedures were approved by the Animal Experimental Committee of Sanwa Kagaku Kenkyusho Co., Ltd. The formalin test is a widely used model that enables two different types of pain to be evaluated: Neurogenic pain is caused by the direct activation of nociceptive nerve terminals, while inflammatory pain is mediated by a combination of peripheral input and spinal cord sensitization. Seven week-old male mice were used for the study (n = 4-5). Formalin (25 μL, 1%) was injected into the plantar surface of the left paw. The time mice spent either licking or lifting the injected paw was recorded at 5 min intervals for 45 min. A test compound suspended in 5% (w/v) aqueous gum arabic or an equal volume of the vehicle was administered by gavage at 17 h and at 1 h before the formalin injection.

In the presently reported formalin test, the first phase (neurogenic phase) was observed 0-10 min after injection; the second phase (inflammatory phase) was then observed 15-45 min after injection [Figure 1]a. Mice treated with TLK48462 showed a significant reduction in paw licking and lifting during the first phase. Furthermore, TLK48462 also significantly reduced the pain during the second phase, compared with that in the control [Figure 1]a and b. The anti-nociceptive effect of TLK48462 was approximately equal to that of indomethacin, which was used as a positive control.{Figure 1}

Next, we examined the effect of TLK48462 using a rat carrageenin model. The injection of carrageenin reportedly induces an inflammatory reaction that produces thermal or mechanical hyperalgesia. Ten week-old male Wistar rats were used for the model (n = 4-5). Inflammation was induced in the rats by the injection of 0.1 mL of 1% λ-carrageenin into the plantar surface of the right hind paw. The test compound suspended in 5% (w/v) aqueous gum arabic or an equal volume of vehicle was then administered by gavage at 17 h and at 1 h before the carrageenin injection.

The nociceptive thresholds were evaluated using the Randall and Selitto method. [6] TLK48462 reduced the carrageenin-induced hyperalgesia. The nociceptive thresholds were measured again at 4 h after the carrageenin challenge. TLK48462 also reduced the hyperalgesia at this time [Figure 2].{Figure 2}

In this study, we confirmed the anti-nociceptive effect of TLK48462 using both formalin and carrageenin models, which we used to evaluate formalin-induced paw edema and carrageenin-induced paw edema, respectively. Interestingly, TLK48462 did not reduce formalin and carrageenin-induced paw edema (data not shown). These results suggest that TLK48462 reduces pain reactions without affecting the acute inflammatory reactions induced by formalin or carrageenin.

 Conclusion



We revealed that TLK48462 reduced formalin-induced or carrageenin-induced pain reactions. Consequently, CCR2/CCR5 antagonists may be useful as a new therapeutic strategy for treating pain.

 Acknowledgment



We thank Dr. Steve Schow for manuscript preparation. We also thank Telik, Inc., for providing TLK48462.

References

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