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Comparative Study
. 2002 Jul 1;22(13):5687-93.
doi: 10.1523/JNEUROSCI.22-13-05687.2002.

Stimulation of deep somatic tissue with capsaicin produces long-lasting mechanical allodynia and heat hypoalgesia that depends on early activation of the cAMP pathway

K A Sluka  1
Affiliations
Comparative Study

Stimulation of deep somatic tissue with capsaicin produces long-lasting mechanical allodynia and heat hypoalgesia that depends on early activation of the cAMP pathway

K A Sluka. J Neurosci. .

Abstract

Pain and hyperalgesia from deep somatic tissue (i.e., muscle and joint) are processed differently from that from skin. This study examined differences between deep and cutaneous tissue allodynia and the role of cAMP in associated behavioral changes. Capsaicin was injected into the plantar aspect of the skin, plantar muscles of the paw, or ankle joint, and responses to mechanical and heat stimuli were assessed until allodynia resolved. Capsaicin injected into skin resulted in a secondary mechanical allodynia and heat hypoalgesia lasting approximately 3 hr. In contrast, capsaicin injection into muscle or joint resulted in a long-lasting bilateral (1-4 weeks) mechanical allodynia with a simultaneous unilateral heat hypoalgesia. The pattern and degree of inflammation were similar when capsaicin was injected into skin, muscle, or joint, with peak increases 24 hr after injection. Heat hypoalgesia that occurs after injection into deep tissue was reversed by spinal blockade of adenylate cyclase or protein kinase A (PKA). Interestingly, mechanical allodynia was reversed if adenylate cyclase or PKA inhibitors were administered spinally 24 hr, but not 1 week, after injection of capsaicin. Spinally administered 8-bromo-cAMP resulted in a similar pattern, with heat hypoalgesia and mechanical allodynia occurring simultaneously. Thus, injection of capsaicin into deep tissues results in a longer-lasting mechanical allodynia and heat hypoalgesia compared with injection of capsaicin into skin. The mechanical allodynia depends on early activation of the cAMP pathway during the first 24 hr but is independent of the cAMP pathway by 1 week after injection of capsaicin.

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Figures

Fig. 1.
Fig. 1.
The paw withdrawal latency to heat (top) and withdrawal threshold to mechanical stimulation (bottom) are shown before and for 4 hr after injection of capsaicin into the skin (squares), muscle (triangles), or joint (circles) for the ipsilateral (closed symbols) or the contralateral (open symbols) side. Significant increases in withdrawal latency to heat ipsilaterally occur after injection of capsaicin into the skin, muscle, or joint. No changes are observed for the contralateral paw. *p < 0.05, significantly different from before capsaicin injection.
Fig. 2.
Fig. 2.
Responses to mechanical and heat stimuli after injection of capsaicin into the ankle joint or plantar muscles of the foot for the ipsilateral (closed circles) and contralateral (open circles) paws. Significant bilateral decreases in withdrawal threshold to mechanical stimuli are evident through 6 weeks after injection into the ankle joint and 1 week after injection into the plantar muscles. The response to heat is elevated ipsilaterally for 6 weeks after injection into the ankle joint and 2 weeks after injection into the plantar muscles. *p< 0.05, significantly different from baseline.
Fig. 3.
Fig. 3.
Withdrawal latency to heat ipsilaterally after spinal blockade with SQ22536 or PKI at 24 hr (top) or 1 week (bottom). A dose-dependent reduction in the capsaicin-induced increased withdrawal latency to heat is observed after spinal blockade of adenylate cyclase with SQ22536 or PKA with PKI. *p < 0.05, significantly different from vehicle control.
Fig. 4.
Fig. 4.
Withdrawal threshold to mechanical stimuli bilaterally 24 hr and 1 week after injection of capsaicin. After spinal blockade with SQ22536 or PKI at 24 hr (top), there is a dose-dependent inhibition of the capsaicin-induced decrease in the withdrawal threshold to mechanical stimuli for animals injected with capsaicin into the muscle (squares) or joint (circles). No effect of SQ22536 or PKI occurred when they were administered 1 week after injection of capsaicin for either the ipsilateral or contralateral paw (bottom). The contralateral side is depicted with open symbols, and the ipsilateral side is depicted with closed symbols. *p < 0.05, significantly different from vehicle control.
Fig. 5.
Fig. 5.
Intrathecal administration of 8-bromo-cAMP resulted in a simultaneous increase in the withdrawal latency to heat and a decrease in the withdrawal threshold to mechanical stimuli compared with baseline. Pretreatment with 60 nmol of PKI prevented the increase in withdrawal latency to heat and the decrease in withdrawal threshold to mechanical stimuli produced by 30 nmol of 8-bromo-cAMP. *p < 0.05, significantly different from baseline;+p < 0.05, significantly different from 30 nmol of 8-bromo-cAMP.
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