The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance

As the incidence and survival rates of patients with cancer continues to
grow, an increasing number of people are living with comorbidities, which
often manifests as cancer-induced bone pain (CIBP). The majority of
patients with CIBP report poor pain control from currently available
analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be
an antinociceptive agent in postsurgical and neuropathic pain states via a
neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and
side effect profile of CGX have never been assessed in CIBP. Here, we
evaluated CGX’s antinociceptive potential in a rodent model of CIBP. We
hypothesized that CGX engages the NTSR2 pathway, providing pain relief
with minimal tolerance and motor side effects. Our results demonstrated
that CGX intrathecal injection in mice with CIBP attenuated both
spontaneous pain behaviors and evoked mechanical hypersensitivity,
regardless of their sex. Furthermore, the antinociceptive effect of CGX
was dependent upon expression of NTSR2 and the R-type voltage-gated
calcium channel (Cav2.3); gene editing of these targets abolished CGX
antinociception without affecting morphine antinociception. Examination of
the side effect profile of CGX demonstrated that, unlike morphine, chronic
intrathecal infusion maintained antinociception with reduced tolerance in
rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on
motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting
analysis revealed expression of NTSR2 in both dorsal and ventral horns,
while Cav2.3 was minimally expressed in the ventral horn, possibly
explaining the sensory selectivity of CGX. Together, these findings
support advancing CGX as a potential therapeutic for cancer pain.