Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase–positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.

Background: Spinal cord stimulation (SCS) is a useful neuromodulatory technique for treatment of certain neuropathic pain conditions. However, the optimal stimulation parameters remain unclear. Methods: In rats after L5 spinal nerve ligation, the authors compared the inhibitory effects on mechanical hypersensitivity from bipolar SCS of different intensities (20, 40, and 80% motor threshold) and frequencies (50, 1 kHz, and 10 kHz). The authors then compared the effects of 1 and 50 Hz dorsal column stimulation at high- and low-stimulus intensities on conduction properties of afferent Aα/β-fibers and spinal wide-dynamic–range neuronal excitability. Results: Three consecutive daily SCS at different frequencies progressively inhibited mechanical hypersensitivity in an intensity-dependent manner. At 80% motor threshold, the ipsilateral paw withdrawal threshold (% preinjury) increased significantly from pre-SCS measures, beginning with the first day of SCS at the frequencies of 1 kHz (50.2 ± 5.7% from 23.9 ± 2.6%, n = 19, mean ± SEM) and 10 kHz (50.8 ± 4.4% from 27.9 ± 2.3%, n = 17), whereas it was significantly increased beginning on the second day in the 50 Hz group (38.9 ± 4.6% from 23.8 ± 2.1%, n = 17). At high intensity, both 1 and 50 Hz dorsal column stimulation reduced Aα/β-compound action potential size recorded at the sciatic nerve, but only 1 kHz stimulation was partially effective at the lower intensity. The number of actions potentials in C-fiber component of wide-dynamic–range neuronal response to windup-inducing stimulation was significantly decreased after 50 Hz (147.4 ± 23.6 from 228.1 ± 39.0, n = 13), but not 1 kHz (n = 15), dorsal column stimulation. Conclusions: Kilohertz SCS attenuated mechanical hypersensitivity in a time course and amplitude that differed from conventional 50 Hz SCS, and may involve different peripheral and spinal segmental mechanisms.

Background: The sites of action and cellular mechanisms by which spinal cord stimulation reduces neuropathic pain remain unclear. Methods: We examined the effect of bipolar electrical-conditioning stimulation (50 Hz, 0.2 ms, 5 min) of the dorsal column and lumbar dorsal roots on the response properties of spinal wide dynamic range (WDR) neurons in rats after L5 spinal nerve injury. The conditioning stimulation intensity was set at the lowest current that evoked a peak antidromic sciatic Aα/β-compound action potential without inducing an Aδ- or C-compound action potential. Results: Within 15 min of the dorsal column or root conditioning stimulation, the spontaneous activity rate of WDR neurons was significantly reduced in nerve-injured rats. Conditioning stimulation also significantly attenuated WDR neuronal responses to mechanical stimuli in nerve-injured rats and inhibited the C-component of the neuronal response to graded intracutaneous electrical stimuli applied to the receptive field in nerve-injured and sham-operated rats. It is noteworthy that dorsal column stimulation blocked windup of WDR neuronal response to repetitive intracutaneous electrical stimulation (0.5 Hz) in nerve-injured and sham-operated rats, whereas dorsal root stimulation inhibited windup only in sham-operated rats. Therefore, stimulation of putative spinal substrates at A-fiber intensities with parameters similar to those used by patients with spinal cord stimulators attenuated established WDR neuronal hyperexcitability in the neuropathic condition and counteracted activity-dependent increase in neuronal excitability (i.e., windup). Conclusions: These results suggest a potential cellular mechanism underlying spinal cord stimulation-induced pain relief. This in vivo model allows the neurophysiologic basis for spinal cord stimulation-induced analgesia to be studied.

Studies in experimental models and controlled patient trials indicate that opioids are effective in managing neuropathic pain. However, side effects secondary to their central nervous system actions present barriers to their clinical use. Therefore, we examined whether activation of the peripheral mu-opioid receptors (MORs) could effectively alleviate neuropathic pain in rats after L5 spinal nerve ligation (SNL). Systemic loperamide hydrochloride (0.3-10 mg/kg, s.c.), a peripherally acting MOR-preferring agonist, dose-dependently reversed the mechanical allodynia at day 7 post-SNL. This anti-allodynic effect produced by systemic loperamide (1.5mg/kg, s.c.) was blocked by systemic pretreatment with either naloxone hydrochloride (10 mg/kg, i.p.) or methyl-naltrexone (5 mg/kg, i.p.), a peripherally acting MOR-preferring antagonist. It was also blocked by ipsilateral intraplantar pretreatment with methyl-naltrexone (43.5 microg/50 microl) and the highly selective MOR antagonist CTAP (5.5 microg/50 microl). However, this anti-allodynic effect of systemic loperamide was not blocked by intraplantar pretreatment with the delta-opioid receptor antagonist naltrindole hydrochloride (45.1 microg/50 microl). The anti-allodynic potency of systemic loperamide varied with time after nerve injury, with similar potency at days 7, 28, and 42 post-SNL, but reduced potency at day 14 post-SNL. Ipsilateral intraplantar injection of loperamide also dose-dependently (10-100 microg/50 microl) reversed mechanical allodynia on day 7 post-SNL. We suggest that loperamide can effectively attenuate neuropathic pain, primarily through activation of peripheral MORs in local tissue. Therefore, peripherally acting MOR agonists may represent a promising therapeutic approach for alleviating neuropathic pain.