Opioid receptor desensitization contributes to thermal hyperalgesia in infant rats

Abstract

Central nociceptive processing includes spinal and supraspinal neurons, but the supraspinal mechanisms mediating changes in pain threshold remain unclear. We investigated the role of forebrain neurons in capsaicin-induced hyperalgesia. Long-Evans rat pups at 21 days were randomized to undisturbed control group, or to receive tactile stimulation, saline injection (0.9% w/v) or capsaicin injection (0.01% w/v) applied to each paw at hourly intervals. Thermal paw withdrawal latency was measured 1 h later, forebrains were removed and purified forebrain neuronal membranes were assayed for adenylyl cyclase activity and opioid receptor function. Capsaicin-injected rats had decreased thermal latency (P < 0.0001) compared to the other groups. Neuronal membranes showed increased basal (P = 0.0003) and forskolin-stimulated (P=0.0002) adenylyl cyclase activity in the capsaicin group compared to other groups. The selective mu-opioid receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) was less effective in inhibiting adenylyl cyclase activity in the capsaicin group (P < 0.001) compared to other groups. These effects were naloxone-reversible and pertussis toxin-sensitive (P < 0.01) in the control, tactile stimulation and saline injection groups but not in the capsaicin group. Binding capacity and affinity for micro-opioid receptors were similar in all four groups, suggesting that receptor downregulation was not involved. Exposure to DAMGO increased [35S]GTPgammaS binding to neuronal membranes from the control, tactile and saline groups (P<0.001) in a naloxone-reversible and pertussis toxin-sensitive manner (P < 0.01) but not in the capsaicin group, suggesting mu-opioid receptor desensitization. Dose responses to systemic morphine were also reduced in the capsaicin group compared to the tactile group (P < 0.05). Capsaicin-induced hyperalgesia in 21-day-old rats was associated with an uncoupling of micro-opioid receptors in the forebrain. Opioid receptor desensitization in the forebrain may reduce opioidergic inputs to the descending inhibitory controls, associated with behavioral hyperalgesia and reduced responsiveness to morphine analgesia in capsaicin-injected young rats.